Journal articles on the topic 'Chemokine biology'
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1
WARD, Stephen G., and John WESTWICK. "Chemokines: understanding their role in T-lymphocyte biology." Biochemical Journal 333, no. 3 (August 1, 1998): 457–70. http://dx.doi.org/10.1042/bj3330457.
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The chemokines are a complex superfamily of small, secreted proteins that were initially characterized through their chemotactic effects on a variety of leucocytes. The superfamily is divided into families based on structural and genetic considerations and have been termed the CXC, CC, C and CX3C families. Chemokines from these families have a key role in the recruitment and function of T lymphocytes. Moreover, T lymphocytes have also been identified as a source of a number of chemokines. T lymphocytes also express most of the known CXC and CC chemokine receptors to an extent that depends on their state of activation/differentiation and/or the activating stimuli. The expression of two chemokine receptors, namely CXCR4 and CCR5, together with the regulated production of their respective ligands, appears to be extremely important in determining sensitivity of T cells to HIV-1 infection. The intracellular events which mediate the effects of chemokines, particularly those elicited by the CC chemokine RANTES, include activation of both G-protein- and protein tyrosine kinase-coupled signalling pathways. The present review describes our current understanding of the structure and expression of chemokines and their receptors, the effects of chemokines on T-cell function(s), the intracellular signalling pathways activated by chemokines and the role of certain chemokines and chemokine receptors in determining sensitivity to HIV-1 infection.
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Schwartzkopff, Franziska, Frank Petersen, Tobias Alexander Grimm, and Ernst Brandt. "CXC chemokine ligand 4 (CXCL4) down-regulates CC chemokine receptor expression on human monocytes." Innate Immunity 18, no. 1 (November 18, 2010): 124–39. http://dx.doi.org/10.1177/1753425910388833.
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During acute inflammation, monocytes are essential in abolishing invading micro-organisms and encouraging wound healing. Recruitment by CC chemokines is an important step in targeting monocytes to the inflamed tissue. However, cell surface expression of the corresponding chemokine receptors is subject to regulation by various endogenous stimuli which so far have not been comprehensively identified. We report that the platelet-derived CXC chemokine ligand 4 (CXCL4), a known activator of human monocytes, induces down-regulation of CC chemokine receptors (CCR) 1, −2, and −5, resulting in drastic impairment of monocyte chemotactic migration towards cognate CC chemokine ligands (CCL) for these receptors. Interestingly, CXCL4-mediated down-regulation of CCR1, CCR2 and CCR5 was strongly dependent on the chemokine’s ability to stimulate autocrine/paracrine release of TNF-α. In turn, TNF-α induced the secretion CCL3 and CCL4, two chemokines selective for CCR1 and CCR5, while the secretion of CCR2-ligand CCL2 was TNF-α-independent. Culture supernatants of CXCL4-stimulated monocytes as well as chemokine-enriched preparations thereof reproduced CXCL4-induced CCR down-regulation. In conclusion, CXCL4 may act as a selective regulator of monocyte migration by stimulating the release of autocrine, receptor-desensitizing chemokine ligands. Our results stress a co-ordinating role for CXCL4 in the cross-talk between platelets and monocytes during early inflammation.
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Liu, Dongxiang, Navid Madani, Ying Li, Rong Cao, Won-Tak Choi, Sameer P. Kawatkar, Mi Youn Lim, et al. "Crystal Structure and Structural Mechanism of a Novel Anti-Human Immunodeficiency Virus and d-Amino Acid-Containing Chemokine." Journal of Virology 81, no. 20 (August 8, 2007): 11489–98. http://dx.doi.org/10.1128/jvi.02845-06.
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ABSTRACT Chemokines and their receptors play important roles in normal physiological functions and the pathogeneses of a wide range of human diseases, including the entry of human immunodeficiency virus type 1 (HIV-1). However, the use of natural chemokines to probe receptor biology or to develop therapeutic drugs is limited by their lack of selectivity and the poor understanding of mechanisms in ligand-receptor recognition. We addressed these issues by combining chemical and structural biology in research into molecular recognition and inhibitor design. Specifically, the concepts of chemical biology were used to develop synthetically and modularly modified (SMM) chemokines that are unnatural and yet have properties improved over those of natural chemokines in terms of receptor selectivity, affinity, and the ability to explore receptor functions. This was followed by using structural biology to determine the structural basis for synthetically perturbed ligand-receptor selectivity. As a proof-of-principle for this combined chemical and structural-biology approach, we report a novel d-amino acid-containing SMM-chemokine designed based on the natural chemokine called viral macrophage inflammatory protein II (vMIP-II). The incorporation of unnatural d-amino acids enhanced the affinity of this molecule for CXCR4 but significantly diminished that for CCR5 or CCR2, thus yielding much more selective recognition of CXCR4 than wild-type vMIP-II. This d-amino acid-containing chemokine also showed more potent and specific inhibitory activity against HIV-1 entry via CXCR4 than natural chemokines. Furthermore, the high-resolution crystal structure of this d-amino acid-containing chemokine and a molecular-modeling study of its complex with CXCR4 provided the structure-based mechanism for the selective interaction between the ligand and chemokine receptors and the potent anti-HIV activity of d-amino acid-containing chemokines.
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Kelvin, David J., Dennis F. Michiel, James A. Johnston, Andrew R. Lloyd, Hans Sprenger, Joost J. Oppenheim, and Ji-Ming Wang. "Chemokines and serpentines: the molecular biology of chemokine receptors." Journal of Leukocyte Biology 54, no. 6 (December 1993): 604–12. http://dx.doi.org/10.1002/jlb.54.6.604.
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Borroni, Elena M., Raffaella Bonecchi, and Annalisa M. VanHook. "Science Signaling Podcast: 30 April 2013." Science Signaling 6, no. 273 (April 30, 2013): pc11. http://dx.doi.org/10.1126/scisignal.2004231.
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This Podcast features an interview with Elena M. Borroni and Raffaella Bonecchi, authors of a Research Article that appears in the 30 April 2013 issue of Science Signaling. Chemokines recruit leukocytes to sites of infection and inflammation by binding to chemokine receptors, which are members of the G protein–coupled receptor superfamily, present on the surface of leukocytes. Whereas activation of typical chemokine receptors leads to G protein–dependent signaling that promotes cell migration toward the chemokine source, activation of atypical chemokine receptors does not promote cell migration. Instead, signaling initiated by atypical chemokine receptors contributes to the immune response in other ways. The atypical chemokine receptor D6 is a scavenger that alters the chemokine gradient by binding to and degrading chemokines. Borroni and Bonecchi found that activation of a β-arrestin–dependent signaling pathway was necessary for D6 to act as a chemokine scavenger.
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Caligiuri, Alessandra, Mirella Pastore, Giulia Lori, Chiara Raggi, Giovanni Di Maira, Fabio Marra, and Alessandra Gentilini. "Role of Chemokines in the Biology of Cholangiocarcinoma." Cancers 12, no. 8 (August 7, 2020): 2215. http://dx.doi.org/10.3390/cancers12082215.
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Cholangiocarcinoma (CCA), a heterogeneous tumor with poor prognosis, can arise at any level in the biliary tree. It may derive from epithelial cells in the biliary tracts and peribiliary glands and possibly from progenitor cells or even hepatocytes. Several risk factors are responsible for CCA onset, however an inflammatory milieu nearby the biliary tree represents the most common condition favoring CCA development. Chemokines play a key role in driving the immunological response upon liver injury and may sustain tumor initiation and development. Chemokine receptor-dependent pathways influence the interplay among various cellular components, resulting in remodeling of the hepatic microenvironment towards a pro-inflammatory, pro-fibrogenic, pro-angiogenic and pre-neoplastic setting. Moreover, once tumor develops, chemokine signaling may influence its progression. Here we review the role of chemokines in the regulation of CCA development and progression, and the modulation of angiogenesis, metastasis and immune control. The potential role of chemokines and their receptors as possible biomarkers and/or therapeutic targets for hepatobiliary cancer is also discussed.
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Gustavsson, Martin, Douglas P. Dyer, Chunxia Zhao, and Tracy M. Handel. "Kinetics of CXCL12 binding to atypical chemokine receptor 3 reveal a role for the receptor N terminus in chemokine binding." Science Signaling 12, no. 598 (September 10, 2019): eaaw3657. http://dx.doi.org/10.1126/scisignal.aaw3657.
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Chemokines bind to membrane-spanning chemokine receptors, which signal through G proteins and promote cell migration. However, atypical chemokine receptor 3 (ACKR3) does not appear to couple to G proteins, and instead of directly promoting cell migration, it regulates the extracellular concentration of chemokines that it shares with the G protein–coupled receptors (GPCRs) CXCR3 and CXCR4, thereby influencing the responses of these receptors. Understanding how these receptors bind their ligands is important for understanding these different processes. Here, we applied association and dissociation kinetic measurements coupled to β-arrestin recruitment assays to investigate ACKR3:chemokine interactions. Our results showed that CXCL12 binding is unusually slow and driven by the interplay between multiple binding epitopes. We also found that the amino terminus of the receptor played a key role in chemokine binding and activation by preventing chemokine dissociation. It was thought that chemokines initially bind receptors through interactions between the globular domain of the chemokine and the receptor amino terminus, which then guides the chemokine amino terminus into the transmembrane pocket of the receptor to initiate signaling. On the basis of our kinetic data, we propose an alternative mechanism in which the amino terminus of the chemokine initially forms interactions with the extracellular loops and transmembrane pocket of the receptor, which is followed by the receptor amino terminus wrapping around the core of the chemokine to prolong its residence time. These data provide insight into how ACKR3 competes and cooperates with canonical GPCRs in its function as a scavenger receptor.
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Huang, Ziwei, Santosh Kumar, Won-Tak Choi, Navid Madani, Chang-Zhi Dong, Dongxiang Liu, Jun Wang, Jing An, and Joseph G. Sodroski. "A New Class of Chemokine Analogs as Useful Research Tools to Study Chemokine Receptor Function and Promising Therapeutic Agents." Blood 104, no. 11 (November 16, 2004): 3839. http://dx.doi.org/10.1182/blood.v104.11.3839.3839.
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Abstract Chemokine receptors play important roles in many physiological processes and are implicated in a wide range of human diseases including acute respiratory distress syndrome, allergic asthma, psoriasis, arthritis, multiple sclerosis, cancer, atherosclerosis and most notably AIDS. To enable the applications of chemokine ligands as probes of receptor biology and pharmacology, and inhibitors of diseases mediated by chemokine receptors, a major problem with the lack of receptor selectivity of these natural chemokines must be overcome. In this study, we have developed a chemical approach combining total protein synthesis and modular modifications to generate a new family of unnatural chemokines termed SMM-chemokines (which refer to synthetically and modularly modified chemokines) with designed receptor selectivity and affinity. A proof of the concept has been provided by applying this strategy to transform a very nonselective chemokine vMIP-II into new analogs with enhanced selectivity and potency for CXCR4 or CCR5, two principal coreceptors for HIV-1 entry. Such novel molecules have been shown subsequently to be valuable probes in gaining insights into receptor binding and signaling mechanisms, and as potent inhibitors to prevent HIV-1 entry and infection. These results strongly support the design concept of these SMM-chemokines and suggest that general applicability of this approach for studying and controlling other chemokine receptors and the diseases they mediate might be anticipated.
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Balkwill, Fran. "Chemokine biology in cancer." Seminars in Immunology 15, no. 1 (February 2003): 49–55. http://dx.doi.org/10.1016/s1044-5323(02)00127-6.
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Luesink, Maaike, Jeroen L. A. Pennings, Willemijn M. Wissink, Peter C. M. Linssen, Petra Muus, Rolph Pfundt, Theo J. M. de Witte, Bert A. van der Reijden, and Joop H. Jansen. "Chemokine induction by all-trans retinoic acid and arsenic trioxide in acute promyelocytic leukemia: triggering the differentiation syndrome." Blood 114, no. 27 (December 24, 2009): 5512–21. http://dx.doi.org/10.1182/blood-2009-02-204834.
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Abstract In acute promyelocytic leukemia (APL), differentiation therapy with all-trans retinoic acid (ATRA) and/or arsenic trioxide can induce a differentiation syndrome (DS) with massive pulmonary infiltration of differentiating leukemic cells. Because chemokines are implicated in migration and extravasation of leukemic cells, chemokines might play a role in DS. ATRA stimulation of the APL cell line NB4 induced expression of multiple CC-chemokines (CCLs) and their receptors (> 19-fold), resulting in increased chemokine levels and chemotaxis. Induction of CCL2 and CCL24 was directly mediated by ligand-activated retinoic acid receptors. In primary leukemia cells derived from APL patients at diagnosis, ATRA induced chemokine production as well. Furthermore, in plasma of an APL patient with DS, we observed chemokine induction, suggesting that chemokines might be important in DS. Dexamethasone, which efficiently reduces pulmonary chemokine production, did not inhibit chemokine induction in APL cells. Finally, chemokine production was also induced by arsenic trioxide as single agent or in combination with ATRA. We propose that differentiation therapy may induce chemokine production in the lung and in APL cells, which both trigger migration of leukemic cells. Because dexamethasone does not efficiently reduce leukemic chemokine production, pulmonary infiltration of leukemic cells may induce an uncontrollable hyperinflammatory reaction in the lung.
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Do, Ha Thi Thu, Chang Hoon Lee, and Jungsook Cho. "Chemokines and their Receptors: Multifaceted Roles in Cancer Progression and Potential Value as Cancer Prognostic Markers." Cancers 12, no. 2 (January 24, 2020): 287. http://dx.doi.org/10.3390/cancers12020287.
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Chemokines are chemotactic cytokines that mediate immune cell chemotaxis and lymphoid tissue development. Recent advances have indicated that chemokines and their cognate receptors play critical roles in cancer-related inflammation and cancer progression. On the basis of these findings, the chemokine system has become a new potential drug target for cancer immunotherapy. In this review, we summarize the essential roles of the complex network of chemokines and their receptors in cancer progression. Furthermore, we discuss the potential value of the chemokine system as a cancer prognostic marker. The chemokine system regulates the infiltration of immune cells into the tumor microenvironment, which induces both pro- and anti-immunity and promotes or suppresses tumor growth and proliferation, angiogenesis, and metastasis. Increasing evidence indicates the promising prognostic value of the chemokine system in cancer patients. While CCL2, CXCL10, and CX3CL1/CX3CR1 can serve as favorable or unfavorable prognostic factors depending on the cancer types, CCL14 and XCL1 possess good prognostic value. Other chemokines such as CXCL1, CXCL8, and CXCL12 are poor prognostic markers. Despite vast advances in our understanding of the complex nature of the chemokine system in tumor biology, knowledge about the multifaceted roles of the chemokine system in different types of cancers is still limited. Further studies are necessary to decipher distinct roles within the chemokine system in terms of cancer progression and to validate their potential value in cancer prognosis.
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Struyf, Sofie, Paul Proost, Jean-Pierre Lenaerts, Griet Stoops, Anja Wuyts, and Jo Van Damme. "Identification of a blood-derived chemoattractant for neutrophils and lymphocytes as a novel CC chemokine, Regakine-1." Blood 97, no. 8 (April 15, 2001): 2197–204. http://dx.doi.org/10.1182/blood.v97.8.2197.
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Abstract Chemokines constitute a large family of chemotactic cytokines that selectively attract different blood cell types. Although most inflammatory chemoattractants are only induced and released in the circulation during acute infection, a restricted number of CXC and CC chemokines are constitutively present in normal plasma at high concentrations. Here, such a chemotactic protein was purified to homogeneity from serum and fully identified as a novel CC chemokine by mass spectrometry and amino acid sequence analysis. The protein, tentatively designated Regakine-1, shows less than 50% sequence identity with any known chemokine. This novel CC chemokine chemoattracts both neutrophils and lymphocytes but not monocytes or eosinophils. Its modest chemotactic potency but high blood concentration is similar to that of other chemokines present in the circulation, such as hemofiltrate CC chemokine-1, platelet factor-4, and β-thromboglobulin. Regakine-1 did not induce neutrophil chemokinesis. However, it synergized with the CXC chemokines interleukin-8 and granulocyte chemotactic protein-2, and the CC chemokine monocyte chemotactic protein-3, resulting in an at least a 2-fold increase of the neutrophil and lymphocyte chemotactic response, respectively. The biologic effects of homogeneous natural Regakine-1 were confirmed with chemically synthesized chemokine. Like other plasma chemokines, it is expected that Regakine-1 plays a unique role in the circulation during normal or pathologic conditions.
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Paoletti, Samantha, Vibor Petkovic, Silvia Sebastiani, M. Gabriela Danelon, Mariagrazia Uguccioni, and Basil O. Gerber. "A rich chemokine environment strongly enhances leukocyte migration and activities." Blood 105, no. 9 (May 1, 2005): 3405–12. http://dx.doi.org/10.1182/blood-2004-04-1648.
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AbstractThe migration of leukocytes in immune surveillance and inflammation is largely determined by their response to chemokines. While the chemokine specificities and expression patterns of chemokine receptors are well defined, it is still a matter of debate how leukocytes integrate the messages provided by different chemokines that are concomitantly produced in physiologic or pathologic situations in vivo. We present evidence for a novel regulatory mechanism of leukocyte trafficking. Our data are consistent with a mode of action where CC-chemokine receptor 7 (CCR7) agonists and unrelated, nonagonist chemokines first form a heteromeric complex, in the presence of which the triggering of CCR7 can occur at a much lower agonist concentration. The increase is synergistic and can be evoked by many but not all chemokines. Chemokine-induced synergism might provide an amplification system in “chemokine-rich” tissues, rendering leukocytes more competent to respond to migratory cues.
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BANAS, BERNHARD, BRUNO LUCKOW, MARCUS MÖLLER, CHRISTIANE KLIER, PETER J. NELSON, ERIK SCHADDE, MANFRED BRIGL, et al. "Chemokine and Chemokine Receptor Expression in a Novel Human Mesangial Cell Line." Journal of the American Society of Nephrology 10, no. 11 (November 1999): 2314–22. http://dx.doi.org/10.1681/asn.v10112314.
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Abstract. Chemokines are thought to play a pivotal role in mediating the selective migration of leukocytes into sites of tissue injury. The local production of chemokines by mesangial cells (MC) has been linked to inflammatory processes within the glomerulus. To study the chemokine biology of human MC, an immortalized human MC line was generated and then chemokine and chemokine receptor expression was examined in response to various proinflammatory stimuli. The results show that human MC have a specific and limited repertoire of chemokine expression. The stimulus-specific regulation of the chemokines monocyte chemoattractant protein-1 (MCP-1), regulated upon activation, normal T cell expressed and secreted (RANTES), interleukin-8 (IL-8), and IP-10 was demonstrated using RNase protection assays. Transcripts for the chemokines MIP-1α, MIP-1β, I-309, or lymphotactin could not be detected. The expression of CC chemokine receptors was investigated by reverse transcription-PCR and RNase protection assays. MC stimulated with interferon-γ (IFN-γ) expressed mRNA for the chemokine receptor CCR1. The expression could be further increased by activating the cells with a combination of tumor necrosis factor-α (TNF-α), IL-1β, and IFN-γ. Under these conditions, no mRNA for CCR2, CCR3, CCR4, CCR5, or CCR8 was detected. A comparison of the immortalized human mesangial cells with primary cells showed identical expression patterns of chemokine receptors. To demonstrate functional activity of chemokine receptors expressed by human MC, chemotaxis assays were performed. MC stimulated with a combination of TNF-α, IL-1β, and IFN-γ, but not unstimulated MC, migrated toward a RANTES gradient. Eotaxin did not enhance the migratory activity of human MC. In summary, a novel human mesangial cell line was established and the pattern of chemokine expression was examined. For the first time, the inducible expression of functionally active CCR1 by human MC was shown.
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Murdoch, Craig, and Adam Finn. "Chemokine receptors and their role in inflammation and infectious diseases." Blood 95, no. 10 (May 15, 2000): 3032–43. http://dx.doi.org/10.1182/blood.v95.10.3032.
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Abstract Chemokines are small peptides that are potent activators and chemoattractants for leukocyte subpopulations and some nonhemopoietic cells. Their actions are mediated by a family of 7-transmembrane G-protein–coupled receptors, the size of which has grown considerably in recent years and now includes 18 members. Chemokine receptor expression on different cell types and their binding and response to specific chemokines are highly variable. Significant advances have been made in understanding the regulation of chemokine receptor expression and the intracellular signaling mechanisms used in bringing about cell activation. Chemokine receptors have also recently been implicated in several disease states including allergy, psoriasis, atherosclerosis, and malaria. However, most fascinating has been the observation that some of these receptors are used by human immunodeficiency virus type 1 in gaining entry into permissive cells. This review will discuss structural and functional aspects of chemokine receptor biology and will consider the roles these receptors play in inflammation and in infectious diseases.
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Murdoch, Craig, and Adam Finn. "Chemokine receptors and their role in inflammation and infectious diseases." Blood 95, no. 10 (May 15, 2000): 3032–43. http://dx.doi.org/10.1182/blood.v95.10.3032.010k17_3032_3043.
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Chemokines are small peptides that are potent activators and chemoattractants for leukocyte subpopulations and some nonhemopoietic cells. Their actions are mediated by a family of 7-transmembrane G-protein–coupled receptors, the size of which has grown considerably in recent years and now includes 18 members. Chemokine receptor expression on different cell types and their binding and response to specific chemokines are highly variable. Significant advances have been made in understanding the regulation of chemokine receptor expression and the intracellular signaling mechanisms used in bringing about cell activation. Chemokine receptors have also recently been implicated in several disease states including allergy, psoriasis, atherosclerosis, and malaria. However, most fascinating has been the observation that some of these receptors are used by human immunodeficiency virus type 1 in gaining entry into permissive cells. This review will discuss structural and functional aspects of chemokine receptor biology and will consider the roles these receptors play in inflammation and in infectious diseases.
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Kramp, Birgit K., Alisina Sarabi, Rory R. Koenen, and Christian Weber. "Heterophilic chemokine receptor interactions in chemokine signaling and biology." Experimental Cell Research 317, no. 5 (March 2011): 655–63. http://dx.doi.org/10.1016/j.yexcr.2010.11.014.
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Cheng, Wenjing, and Guangjie Chen. "Chemokines and Chemokine Receptors in Multiple Sclerosis." Mediators of Inflammation 2014 (2014): 1–8. http://dx.doi.org/10.1155/2014/659206.
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Multiple sclerosis is an autoimmune disease with classical traits of demyelination, axonal damage, and neurodegeneration. The migration of autoimmune T cells and macrophages from blood to central nervous system as well as the destruction of blood brain barrier are thought to be the major processes in the development of this disease. Chemokines, which are small peptide mediators, can attract pathogenic cells to the sites of inflammation. Each helper T cell subset expresses different chemokine receptors so as to exert their different functions in the pathogenesis of MS. Recently published results have shown that the levels of some chemokines and chemokine receptors are increased in blood and cerebrospinal fluid of MS patients. This review describes the advanced researches on the role of chemokines and chemokine receptors in the development of MS and discusses the potential therapy of this disease targeting the chemokine network.
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Sun, Jia, Raina Devi Ramnath, and Madhav Bhatia. "Neuropeptide substance P upregulates chemokine and chemokine receptor expression in primary mouse neutrophils." American Journal of Physiology-Cell Physiology 293, no. 2 (August 2007): C696—C704. http://dx.doi.org/10.1152/ajpcell.00060.2007.
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Neuropeptides play an important role in the active communication between the nervous and immune systems. Substance P (SP) is a prominent neuropeptide involved in neurogenic inflammation and has been reported to exert various proinflammatory actions on inflammatory leukocytes including neutrophils. The present study further investigated the modulatory effect of SP (1 μM) on chemokine production and chemokine receptor expression in primary mouse neutrophils. Our results showed that SP primed neutrophils for chemotactic responses not only to the CXC chemokine macrophage inflammatory protein (MIP)-2/CXCL2 but also to the CC chemokine MIP-1α/CCL3. The activating effect of SP on neutrophils was further evidenced by upregulation of the CD11b integrin, the activation marker of neutrophils. SP induced both the mRNA and protein expression of the chemokines MIP-1α/CCL3 and MIP-2/CXCL2 in neutrophils and upregulated the chemokine receptors CC chemokine receptor (CCR)-1 and CXC chemokine receptor (CXCR)-2. This stimulatory effect on chemokine and chemokine receptor expression in neutrophils was further found to be neurokinin-1 receptor (NK-1R) specific. Pretreatment with selective NK-1R antagonists inhibited SP-triggered activation of neutrophils and chemokine and chemokine receptor upregulation. Moreover, SP-induced chemokine upregulation was NF-κB dependent. SP time dependently induced NF-κB p65 binding activity, IκBα degradation, and NF-κB p65 nuclear translocation in neutrophils. Inhibition of NF-κB activation with its inhibitor Bay11-7082 (10 μM) abolished SP-induced NF-κB binding activity and upregulation of MIP-1α/CCL3 and MIP-2/CXCL2 in neutrophils. Together, these results suggest that SP exerts a direct stimulatory effect on the expression of chemokines and chemokine receptors in mouse neutrophils. The effect is NK-1R mediated, involving NF-κB activation.
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Mackay, Charles R. "Chemokines: What chemokine is that?" Current Biology 7, no. 6 (June 1997): R384—R386. http://dx.doi.org/10.1016/s0960-9822(06)00181-3.
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Miyagawa, Fumi, and Hideo Asada. "Chemokines in Severe Cutaneous Adverse Reactions (SCARs)." Biomolecules 11, no. 6 (June 6, 2021): 847. http://dx.doi.org/10.3390/biom11060847.
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Although the incidence of severe cutaneous adverse reactions (SCARs) to medications is very low, SCARs can result in disability or even death if they are not diagnosed and treated properly. As the rapid recognition of SCARs is essential, it is necessary to develop diagnostic markers for them that can also be used to assess severity and predict outcomes in the early phase. In addition, it is important to identify novel therapeutic targets for SCARs. Chemokines are chemotactic cytokines that control the migratory patterns and locations of immune cells and usually exhibit markedly specific associations with certain human diseases. In Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN), the Th1-associated chemokines chemokine (C-X-C motif) ligand 9 (CXCL9) and CXCL10 predominate, while in drug-induced hypersensitivity syndrome (DIHS)/drug reaction with eosinophilia and systemic symptoms (DRESS), the levels of the Th2-associated chemokines chemokine (C-C motif) ligand 17 (CCL17) and CCL22 are markedly elevated. We suggest that the distinct chemokine profiles of SJS/TEN and DIHS/DRESS can be used to aid their differential diagnosis. CXCL10 has also been reported to be associated with the development of long-term sequelae in DIHS/DRESS. This review focuses on the chemokines involved in the pathogenesis and adjuvant diagnosis of SCARs, particularly SJS/TEN and DIHS/DRESS, but also provides a brief overview of SCARs and the chemokine superfamily. As it is being increasingly recognized that an association exists between human herpesvirus 6 (HHV-6) and DIHS/DRESS, the possible roles of the chemokine/chemokine receptor homologs encoded by HHV-6 in the pathogenesis of DIHS/DRESS are also discussed.
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Mahalingam, Surendran, and Gunasegaran Karupiah. "Chemokines and chemokine receptors in infectious diseases." Immunology and Cell Biology 77, no. 6 (December 1999): 469–75. http://dx.doi.org/10.1046/j.1440-1711.1999.00858.x.
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Bule, Pedro, Sandra Isabel Aguiar, Frederico Aires-Da-Silva, and Joana Nunes Ribeiro Dias. "Chemokine-Directed Tumor Microenvironment Modulation in Cancer Immunotherapy." International Journal of Molecular Sciences 22, no. 18 (September 10, 2021): 9804. http://dx.doi.org/10.3390/ijms22189804.
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Chemokines are a large family of small chemotactic cytokines that coordinates immune cell trafficking. In cancer, they have a pivotal role in the migration pattern of immune cells into the tumor, thereby shaping the tumor microenvironment immune profile, often towards a pro-tumorigenic state. Furthermore, chemokines can directly target non-immune cells in the tumor microenvironment, including cancer, stromal and vascular endothelial cells. As such, chemokines participate in several cancer development processes such as angiogenesis, metastasis, cancer cell proliferation, stemness and invasiveness, and are therefore key determinants of disease progression, with a strong influence in patient prognosis and response to therapy. Due to their multifaceted role in the tumor immune response and tumor biology, the chemokine network has emerged as a potential immunotherapy target. Under the present review, we provide a general overview of chemokine effects on several tumoral processes, as well as a description of the currently available chemokine-directed therapies, highlighting their potential both as monotherapy or in combination with standard chemotherapy or other immunotherapies. Finally, we discuss the most critical challenges and prospects of developing targeted chemokines as therapeutic options.
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Choi, Young Bong, and John Nicholas. "Autocrine and Paracrine Promotion of Cell Survival and Virus Replication by Human Herpesvirus 8 Chemokines." Journal of Virology 82, no. 13 (April 23, 2008): 6501–13. http://dx.doi.org/10.1128/jvi.02396-07.
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ABSTRACT Human herpesvirus 8 (HHV-8), which is associated with the endothelial tumor Kaposi's sarcoma, encodes three CC/β-chemokines. These are expressed early during productive (lytic) infection and are believed to be involved in immune evasion, in addition to viral pathogenesis via induction of angiogenic cytokines. Here we report that two of the HHV-8 chemokines, CCR8 agonists vCCL-1 and vCCL-2, have direct effects on endothelial survival and virus replication. The v-chemokines stimulated virus replication when added to infected cultures exogenously, and CCR8 knockdown absent v-chemokine supplementation inhibited virus production, indicative of autocrine effects of endogenously produced vCCLs. This was verified and proreplication functions of each chemokine were demonstrated via shRNA-mediated vCCL depletion. The v-chemokines inhibited expression of lytic cycle-induced proapoptotic protein Bim, RNA interference-mediated suppression of which mimicked v-chemokine proreplication functions. Our data show for the first time that the v-chemokines have direct effects on virus biology, independently of their postulated immune evasion functions, and suggest that in vivo the v-chemokines might play direct roles in Kaposi's sarcomagenesis via paracrine prosurvival signaling.
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Borroni, Elena M., Cinzia Cancellieri, Alessandro Vacchini, Yann Benureau, Bernard Lagane, Françoise Bachelerie, Fernando Arenzana-Seisdedos, et al. "β-Arrestin–Dependent Activation of the Cofilin Pathway Is Required for the Scavenging Activity of the Atypical Chemokine Receptor D6." Science Signaling 6, no. 273 (April 30, 2013): ra30. http://dx.doi.org/10.1126/scisignal.2003627.
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Chemokines promote the recruitment of leukocytes to sites of infection and inflammation by activating conventional heterotrimeric guanine nucleotide–binding protein (G protein)–coupled receptors (GPCRs). Chemokines are also recognized by a set of atypical chemokine receptors (ACRs), which cannot induce directional cell migration but are required for the generation of chemokine gradients in tissues. ACRs are presently considered “silent receptors” because no G protein–dependent signaling activity is observed after their engagement by cognate ligands. We report that engagement of the ACR D6 by its ligands activates a β-arrestin1–dependent, G protein–independent signaling pathway that results in the phosphorylation of the actin-binding protein cofilin through the Rac1–p21-activated kinase 1 (PAK1)–LIM kinase 1 (LIMK1) cascade. This signaling pathway is required for the increased abundance of D6 protein at the cell surface and for its chemokine-scavenging activity. We conclude that D6 is a signaling receptor that exerts its regulatory function on chemokine-mediated responses in inflammation and immunity through a distinct signaling pathway.
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Jin, Hongjun, Xiaohong Shen, Brandi Renee Baggett, Xiangming Kong, and Patricia J. LiWang. "The Human CC Chemokine MIP-1β Dimer Is Not Competent to Bind to the CCR5 Receptor." Journal of Biological Chemistry 282, no. 38 (July 20, 2007): 27976–83. http://dx.doi.org/10.1074/jbc.m702654200.
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Chemokine dimerization has been the subject of much interest in recent years as evidence has accumulated that different quaternary states of chemokines play different biological roles; the monomer is believed to be the receptor-binding unit, whereas the dimer has been implicated in binding cell surface glycosaminoglycans. However, although several studies have provided evidence for this paradigm by making monomeric chemokine variants or dimer-impaired chemokines, few have provided direct evidence of the receptor function of a chemokine dimer. We have produced a covalent dimer of the CC chemokine macrophage inflammatory protein-1β (MIP-1β) by placing a disulfide bond at the center of its dimer interface through a single amino acid substitution (MIP-1β-A10C). This variant was shown to be a nondissociating dimer by SDS-PAGE and analytical ultracentrifugation. NMR reveals a structure largely the same as the wild type protein. In studies of glycosaminoglycan binding, MIP-1β-A10C binds to a heparin-Sepharose column as tightly as the wild type protein and more tightly than monomeric variants. However, MIP-1β-A10C neither binds nor activates the MIP-1β receptor CCR5. It was found that the ability to activate CCR5 was recovered upon reduction of the intermolecular disulfide cross-link by incubation with 1 mm dithiothreitol. This work provides the first definitive evidence that the CC chemokine MIP-1β dimer is not able to bind or activate its receptor and implicates the CC chemokine monomer as the sole receptor-interacting unit.
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Neote, K., JY Mak, LF Jr Kolakowski, and TJ Schall. "Functional and biochemical analysis of the cloned Duffy antigen: identity with the red blood cell chemokine receptor." Blood 84, no. 1 (July 1, 1994): 44–52. http://dx.doi.org/10.1182/blood.v84.1.44.44.
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Abstract The Duffy blood group antigen has been postulated to be a receptor on red blood cells (RBCs) for the malarial parasite Plasmodium vivax and a promiscuous receptor for the chemokine superfamily of inflammatory proteins. Recently, the Duffy antigen glycoprotein D cDNA has been cloned (Chaudhuri et al: Proc Natl Acad Sci USA 90:10793, 1993). We have analyzed the binding properties of the cloned Duffy antigen. Duffy- antigen cDNAs expressed in human embryonic kidney cells produced cell- surface proteins that reacted with two known anti-Duffy monoclonal antibodies. Direct ligand binding and displacement experiments using recombinant chemokine proteins also show that the cloned Duffy protein is the RBC chemokine receptor. Radiolabeled chemokines of both the C-C (RANTES and MCP-1) and C-X-C (IL-8 and MGSA/gro) subclasses bound reversibly to transfected cells with dissociation constants in the nanomolar range. Chemokines of either class displaced heterologous chemokines, indicating that they were competing for a single site on the transfected cells. Although the chemokines bound to the transfected cells with high affinity, there was no evidence for signal transduction, as measured by transient increases in intracellular calcium ion concentration, through the Duffy antigen/RBC chemokine receptor in transfected cells. Lastly, we have performed a computer analysis on the amino acid structure of the Duffy antigen/RBC chemokine receptor. Although the cloned Duffy antigen has been postulated to be a nine-transmembrane-spanning receptor, our analysis suggests that the molecule most likely belongs to the seven-transmembrane-spanning receptor superfamily and is therefore similar to other chemokine receptors previously identified.
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Neote, K., JY Mak, LF Jr Kolakowski, and TJ Schall. "Functional and biochemical analysis of the cloned Duffy antigen: identity with the red blood cell chemokine receptor." Blood 84, no. 1 (July 1, 1994): 44–52. http://dx.doi.org/10.1182/blood.v84.1.44.bloodjournal84144.
Full textAbstract:
The Duffy blood group antigen has been postulated to be a receptor on red blood cells (RBCs) for the malarial parasite Plasmodium vivax and a promiscuous receptor for the chemokine superfamily of inflammatory proteins. Recently, the Duffy antigen glycoprotein D cDNA has been cloned (Chaudhuri et al: Proc Natl Acad Sci USA 90:10793, 1993). We have analyzed the binding properties of the cloned Duffy antigen. Duffy- antigen cDNAs expressed in human embryonic kidney cells produced cell- surface proteins that reacted with two known anti-Duffy monoclonal antibodies. Direct ligand binding and displacement experiments using recombinant chemokine proteins also show that the cloned Duffy protein is the RBC chemokine receptor. Radiolabeled chemokines of both the C-C (RANTES and MCP-1) and C-X-C (IL-8 and MGSA/gro) subclasses bound reversibly to transfected cells with dissociation constants in the nanomolar range. Chemokines of either class displaced heterologous chemokines, indicating that they were competing for a single site on the transfected cells. Although the chemokines bound to the transfected cells with high affinity, there was no evidence for signal transduction, as measured by transient increases in intracellular calcium ion concentration, through the Duffy antigen/RBC chemokine receptor in transfected cells. Lastly, we have performed a computer analysis on the amino acid structure of the Duffy antigen/RBC chemokine receptor. Although the cloned Duffy antigen has been postulated to be a nine-transmembrane-spanning receptor, our analysis suggests that the molecule most likely belongs to the seven-transmembrane-spanning receptor superfamily and is therefore similar to other chemokine receptors previously identified.
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Loos, Tamara, Anneleen Mortier, Mieke Gouwy, Isabelle Ronsse, Willy Put, Jean-Pierre Lenaerts, Jo Van Damme, and Paul Proost. "Citrullination of CXCL10 and CXCL11 by peptidylarginine deiminase: a naturally occurring posttranslational modification of chemokines and new dimension of immunoregulation." Blood 112, no. 7 (October 1, 2008): 2648–56. http://dx.doi.org/10.1182/blood-2008-04-149039.
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Abstract Interactions between chemokines and enzymes are vital in immunoregulation. Structural protein citrullination by peptidylarginine deiminase (PAD) has been associated with autoimmunity. In this report, we identified a novel naturally occurring posttranslational modification of chemokines, that is, the deimination of arginine at position 5 into citrulline of CXC chemokine ligand 10 (CXCL10) by rabbit PAD and human PAD2. Citrullination reduced (≥ 10-fold) the chemoattracting and signaling capacity of CXCL10 for CXC chemokine receptor 3 (CXCR3) transfectants; however, it did not affect CXCR3 binding. On T lymphocytes, though, citrullinated CXCL10 remained active but was again weaker than authentic CXCL10. PAD was also able to convert CXCL11, causing an impairment of CXCR3 signaling and T-cell activation, though less pronounced than for CXCL10. Similarly, receptor binding properties of CXCL11 were not altered by citrullination. However, deimination decreased heparin binding properties of both CXCL10 and CXCL11. Overall, chemokines are the first immune modulators reported of being functionally modified by citrullination. These data provide new structure-function dimensions for chemokines in leukocyte mobilization, disclosing an anti-inflammatory role for PAD. Additionally because citrullination has severe consequences for chemokine biology, this invites to reassess the involvement and impact of PAD and citrullinated peptides in inflammation, autoimmunity, and hematologic disorders.
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Darlot, Benoit, James R. O. Eaton, Lucia Geis-Asteggiante, Gopala K. Yakala, Kalimuthu Karuppanan, Graham Davies, Carol V. Robinson, Akane Kawamura, and Shoumo Bhattacharya. "Engineered anti-inflammatory peptides inspired by mapping an evasin–chemokine interaction." Journal of Biological Chemistry 295, no. 32 (May 29, 2020): 10926–39. http://dx.doi.org/10.1074/jbc.ra120.014103.
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Chemokines mediate leukocyte migration and homeostasis and are key targets in inflammatory diseases including atherosclerosis, cytokine storm, and chronic autoimmune disease. Chemokine redundancy and ensuing network robustness has frustrated therapeutic development. Salivary evasins from ticks bind multiple chemokines to overcome redundancy and are effective in several preclinical disease models. Their clinical development has not progressed because of concerns regarding potential immunogenicity, parenteral delivery, and cost. Peptides mimicking protein activity can overcome the perceived limitations of therapeutic proteins. Here we show that peptides possessing multiple chemokine-binding and anti-inflammatory activities can be developed from the chemokine-binding site of an evasin. We used hydrogen–deuterium exchange MS to map the binding interface of the evasin P672 that physically interacts with C–C motif chemokine ligand (CCL) 8 and synthesized a 16-mer peptide (BK1.1) based on this interface region in evasin P672. Fluorescent polarization and native MS approaches showed that BK1.1 binds CCL8, CCL7, and CCL18 and disrupts CCL8 homodimerization. We show that a BK1.1 derivative, BK1.3, has substantially improved ability to disrupt P672 binding to CCL8, CCL2, and CCL3 in an AlphaScreen assay. Using isothermal titration calorimetry, we show that BK1.3 directly binds CCL8. BK1.3 also has substantially improved ability to inhibit CCL8, CCL7, CCL2, and CCL3 chemotactic function in vitro. We show that local as well as systemic administration of BK1.3 potently blocks inflammation in vivo. Identification and characterization of the chemokine-binding interface of evasins could thus inspire the development of novel anti-inflammatory peptides that therapeutically target the chemokine network in inflammatory diseases.
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Locati, MD, Massimo, and Philip M. Murphy, MD. "CHEMOKINES AND CHEMOKINE RECEPTORS: Biology and Clinical Relevance in Inflammation and AIDS." Annual Review of Medicine 50, no. 1 (February 1999): 425–40. http://dx.doi.org/10.1146/annurev.med.50.1.425.
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Pease, James E. "Targeting chemokine receptors in allergic disease." Biochemical Journal 434, no. 1 (January 27, 2011): 11–24. http://dx.doi.org/10.1042/bj20101132.
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The directed migration of cells in response to chemical cues is known as chemoattraction, and plays a key role in the temporal and spatial positioning of cells in lower- and higher-order life forms. Key molecules in this process are the chemotactic cytokines, or chemokines, which, in humans, constitute a family of approx. 40 molecules. Chemokines exert their effects by binding to specific GPCRs (G-protein-coupled receptors) which are present on a wide variety of mature cells and their progenitors, notably leucocytes. The inappropriate or excessive generation of chemokines is a key component of the inflammatory response observed in several clinically important diseases, notably allergic diseases such as asthma. Consequently, much time and effort has been directed towards understanding which chemokine receptors and ligands are important in the allergic response with a view to therapeutic intervention. Such strategies can take several forms, although, as the superfamily of GPCRs has historically proved amenable to blockade by small molecules, the development of specific antagonists has been has been a major focus of several groups. In the present review, I detail the roles of chemokines and their receptors in allergic disease and also highlight current progress in the development of relevant chemokine receptor antagonists.
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Stumm, Ralf, and Volker Höllt. "CXC chemokine receptor 4 regulates neuronal migration and axonal pathfinding in the developing nervous system: implications for neuronal regeneration in the adult brain." Journal of Molecular Endocrinology 38, no. 3 (March 2007): 377–82. http://dx.doi.org/10.1677/jme-06-0032.
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Chemotactic cytokines (chemokines) are small secreted proteins that control leukocyte trafficking in immune organs. Chemokines which are induced in the brain during conditions of inflammation play a role in the local immune response. Recently, it has been established in the rodent brain that distinct chemokines and chemokine receptors are constitutively expressed by neurons and that these chemokines modulate neuronal functions. The CXC motif chemokine stromal cell-derived factor-1 (SDF-1), CXCL12 together with its cognate receptor CXCR4 represents the best-characterized neuronal chemokine system. Transwell migration assays with neuronal precursors, pharmacological manipulation of CXCR4 signaling in embryonic brain explants, and histochemical studies of SDF-1- or CXCR4-deficient mouse embryos provide proof that SDF-1 directs neuronal migration and axonal pathfinding in the developing nervous system. In the adult brain, SDF-1 is thought to influence neurogenesis as well as recruitment of brain resident and non-resident circulating cells toward sites of lesion. The present review summarizes patterns and functions of the SDF-1/CXCR4 system in the rodent brain with a focus on the developing and adult cerebral cortex.
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Red-Horse, Kristy, Penelope M. Drake, and Susan J. Fisher. "Human pregnancy: the role of chemokine networks at the fetal–maternal interface." Expert Reviews in Molecular Medicine 6, no. 11 (May 7, 2004): 1–14. http://dx.doi.org/10.1017/s1462399404007720.
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Chemokines are multifunctional molecules initially described as having a role in leukocyte trafficking and later found to participate in developmental processes such as differentiation and directed migration. Similar events occur in pregnancy during development of the fetal–maternal interface, where there is extensive leukocyte trafficking and tissue morphogenesis, and this is accompanied by abundant chemokine expression. The relationship between chemokines, leukocytes and placental development is beginning to be delineated. During pregnancy a specialised population of maternal leukocytes infiltrates the implantation site. These leukocytes are thought to sustain the delicate balance between protecting the developing embryo/fetus and tolerating its hemiallogeneic tissues. A network of chemokine expression by both fetal and maternal components in the pregnant uterus functions in establishing this leukocyte population. Intriguingly, experiments investigating immune cell recruitment revealed the additional possibility that chemokines influence aspects of placental development. Specifically, cytotrophoblasts, the effector cells of the placenta, express chemokine receptors that can bind ligands found at key locations, implicating chemokines as regulators of cytotrophoblast differentiation and migration. Thus, as in other systems, at the fetal–maternal interface chemokines might regulate multiple functions.
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Schiavo, Roberta, Dolgor Baatar, Purevdorj Olkhanud, Fred E. Indig, Nicholas Restifo, Dennis Taub, and Arya Biragyn. "Chemokine receptor targeting efficiently directs antigens to MHC class I pathways and elicits antigen-specific CD8+ T-cell responses." Blood 107, no. 12 (June 15, 2006): 4597–605. http://dx.doi.org/10.1182/blood-2005-08-3207.
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Abstract Chemokines are key controllers of cell trafficking and are involved in numerous pathologic and inflammatory conditions. However, the fate of a chemokine ligand, once it is endocytosed with its receptor, remains obscure. Here, using chemokine–tumor antigen fusion constructs, we demonstrate for the first time that chemokines are internalized to early/late endosomal and lysosomal compartments through a clathrin-dependent process and subsequently delivered to the cytosol for proteasomal processing, facilitating efficient cross-presentation to the TAP-1–dependent MHC class I processing pathway. These data not only elucidate the intracellular fate of chemokine ligands upon receptor uptake, but also demonstrate the superior carrier potency of chemokines for delivering self-antigens to both class I and II processing pathways to induce CD8+ and CD4+ T-cell responses.
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Svirshchevskaya, Elena V., Mariya V. Konovalova, Eugene V. Snezhkov, Rimma A. Poltavtseva, and Sergey B. Akopov. "Chemokine Homeostasis in Healthy Volunteers and during Pancreatic and Colorectal Tumor Growth in Murine Models." Current Issues in Molecular Biology 44, no. 10 (October 18, 2022): 4987–99. http://dx.doi.org/10.3390/cimb44100339.
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Chemokines are involved in the humoral regulation of body homeostasis. Changes in the blood level of chemokines were found in cancer, atherosclerosis, diabetes, and other systemic diseases. It is essential to distinguish the effects of co-morbid pathologies and cancer on the level of chemokines in the blood. We aimed to analyze, by multiplex cytometry, the levels of chemokines in the blood of healthy young volunteers as well as of intact mice and mice with CT26 colon and Pan02 pancreatic tumors. Two types of chemokines were identified both in human and murine plasmas: homeostatic ones, which were found in high concentrations (>100 pg/mL), and inducible ones, which can be undetectable or determined at very low levels (0–100 pg/mL). There was a high variability in the chemokine levels, both in healthy humans and mice. To analyze chemokine levels during tumor growth, C57BL/6 and BALB/c were inoculated with Pan02 or CT26 tumor cells, accordingly. The tumors significantly differed in the growth and the mortality of mice. However, the blood chemokine levels did not change in tumor-bearing mice until the very late stages. Taken collectively, blood chemokine level is highly variable and reflects in situ homeostasis. Care should be taken when considering chemokines as prognostic parameters or therapeutic targets in cancer.
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Andjelkovic, Anuska V., Dennis D. Spencer, and Joel S. Pachter. "Visualization of Chemokine Binding Sites on Human Brain Microvessels." Journal of Cell Biology 145, no. 2 (April 19, 1999): 403–12. http://dx.doi.org/10.1083/jcb.145.2.403.
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The chemokines monocyte chemoattractant protein-1 (MCP-1) and macrophage inflammatory protein-1α (MIP-1α) aid in directing leukocytes to specific locales within the brain and spinal cord during central nervous system inflammation. However, it remains unclear how these chemokines exert their actions across a vascular barrier, raising speculation that interaction with endothelial cells might be required. Therefore, experiments were performed to determine whether binding domains for these chemokines exist along the outer surface of brain microvessels, a feature that could potentially relay chemokine signals from brain to blood. Using a biotinylated chemokine binding assay with confocal microscopy and three-dimensional image reconstruction, spatially resolved binding sites for MCP-1 and MIP-α around human brain microvessels were revealed for the first time. Binding of labeled MCP-1 and MIP-1α could be inhibited by unlabeled homologous but not heterologous chemokine, and was independent of the presence of heparan sulfate, laminin, or collagen in the subendothelial matrix. This is the first evidence of specific and separate binding domains for MCP-1 and MIP-1α on the parenchymal surface of microvessels, and highlights the prospect that specific interactions of chemokines with microvascular elements influence the extent and course of central nervous system inflammation.
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Moratz, Chantal, J. Russell Hayman, Hua Gu, and John H. Kehrl. "Abnormal B-Cell Responses to Chemokines, Disturbed Plasma Cell Localization, and Distorted Immune Tissue Architecture in Rgs1−/− Mice." Molecular and Cellular Biology 24, no. 13 (July 1, 2004): 5767–75. http://dx.doi.org/10.1128/mcb.24.13.5767-5775.2004.
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ABSTRACT Normal lymphoid tissue development and function depend upon chemokine-directed cell migration. Since chemokines signal through heterotrimeric G-protein-coupled receptors, RGS proteins, which act as GTPase-activating proteins for Gα subunits, likely fine tune the cellular responses to chemokines. Here we show that Rgs1−/− mice possess B cells that respond excessively and desensitize improperly to the chemokines CXCL12 and CXCL13. Many of the B-cell follicles in the spleens of Rgs1−/− mice have germinal centers even in the absence of immune stimulation. Furthermore, immunization of these mice leads to exaggerated germinal center formation; partial disruption of the normal architecture of the spleen and Peyer's patches; and abnormal trafficking of immunoglobulin-secreting cells. These results reveal the importance of a regulatory mechanism that limits and desensitizes chemokine receptor signaling.
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Sepuru, Krishna Mohan, Balaji Nagarajan, Umesh R. Desai, and Krishna Rajarathnam. "Structural basis, stoichiometry, and thermodynamics of binding of the chemokines KC and MIP2 to the glycosaminoglycan heparin." Journal of Biological Chemistry 293, no. 46 (September 26, 2018): 17817–28. http://dx.doi.org/10.1074/jbc.ra118.004866.
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Keratinocyte-derived chemokine (KC or mCXCL1) and macrophage inflammatory protein 2 (MIP2 or mCXCL2) play nonredundant roles in trafficking blood neutrophils to sites of infection and injury. The functional responses of KC and MIP2 are intimately coupled to their interactions with glycosaminoglycans (GAGs). GAG interactions orchestrate chemokine concentration gradients and modulate receptor activity, which together regulate neutrophil trafficking. Here, using NMR, molecular dynamics (MD) simulations, and isothermal titration calorimetry (ITC), we characterized the molecular basis of KC and MIP2 binding to the GAG heparin. Both chemokines reversibly exist as monomers and dimers, and the NMR analysis indicates that the dimer binds heparin with higher affinity. The ITC experiments indicate a stoichiometry of two GAGs per KC or MIP2 dimer and that the enthalpic and entropic contributions vary significantly between the two chemokine–heparin complexes. NMR-based structural models of heparin–KC and heparin–MIP2 complexes reveal that different combinations of residues from the N-loop, 40s turn, β3-strand, and C-terminal helix form a binding surface within a monomer and that both conserved residues and residues unique to a particular chemokine mediate the binding interactions. MD simulations indicate significant residue-specific differences in their contribution to binding and affinity for a given chemokine and between chemokines. On the basis of our observations that KC and MIP2 bind to GAG via distinct molecular interactions, we propose that the differences in these GAG interactions lead to differences in neutrophil recruitment and play nonoverlapping roles in resolution of inflammation.
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Pelletier, Anthony J., Luc J. W. van der Laan, Patrick Hildbrand, Michael A. Siani, Darren A. Thompson, Philip E. Dawson, Bruce E. Torbett, and Daniel R. Salomon. "Presentation of chemokine SDF-1α by fibronectin mediates directed migration of T cells." Blood 96, no. 8 (October 15, 2000): 2682–90. http://dx.doi.org/10.1182/blood.v96.8.2682.
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Abstract The role of chemokine–matrix interactions in integrin-dependent T-cell migration was examined to address the critical question of how chemokines provide directional information. The chemokine SDF-1α binds fibronectin (Fn) with a low nanomolar Kd(equilibrium dissociation constant). SDF-1α presented by Fn induced directed migration. Spatial concentration gradients of chemokine were not required to maintain directed migration. Fn-presented chemokine induced the polarization of cells, including the redistribution of the SDF-1α receptor, to the basal surface and leading edge of the cell. A new model for directed migration is proposed in which the co-presentation of an adhesive matrix and chemokine provides the necessary positional information independent of a soluble spatial gradient.
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Pelletier, Anthony J., Luc J. W. van der Laan, Patrick Hildbrand, Michael A. Siani, Darren A. Thompson, Philip E. Dawson, Bruce E. Torbett, and Daniel R. Salomon. "Presentation of chemokine SDF-1α by fibronectin mediates directed migration of T cells." Blood 96, no. 8 (October 15, 2000): 2682–90. http://dx.doi.org/10.1182/blood.v96.8.2682.h8002682_2682_2690.
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The role of chemokine–matrix interactions in integrin-dependent T-cell migration was examined to address the critical question of how chemokines provide directional information. The chemokine SDF-1α binds fibronectin (Fn) with a low nanomolar Kd(equilibrium dissociation constant). SDF-1α presented by Fn induced directed migration. Spatial concentration gradients of chemokine were not required to maintain directed migration. Fn-presented chemokine induced the polarization of cells, including the redistribution of the SDF-1α receptor, to the basal surface and leading edge of the cell. A new model for directed migration is proposed in which the co-presentation of an adhesive matrix and chemokine provides the necessary positional information independent of a soluble spatial gradient.
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Berg, Christian, Michael J. Wedemeyer, Motiejus Melynis, Roman R. Schlimgen, Lasse H. Hansen, Jon Våbenø, Francis C. Peterson, Brian F. Volkman, Mette M. Rosenkilde, and Hans R. Lüttichau. "The non-ELR CXC chemokine encoded by human cytomegalovirus UL146 genotype 5 contains a C-terminal β-hairpin and induces neutrophil migration as a selective CXCR2 agonist." PLOS Pathogens 18, no. 3 (March 10, 2022): e1010355. http://dx.doi.org/10.1371/journal.ppat.1010355.
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Human cytomegalovirus (HCMV) is a major pathogen in immunocompromised patients. The UL146 gene exists as 14 diverse genotypes among clinical isolates, which encode 14 different CXC chemokines. One genotype (vCXCL1GT1) is a known agonist for CXCR1 and CXCR2, while two others (vCXCL1GT5 and vCXCL1GT6) lack the ELR motif considered crucial for CXCR1 and CXCR2 binding, thus suggesting another receptor targeting profile. To determine the receptor target for vCXCL1GT5, the chemokine was probed in a G protein signaling assay on all 18 classical human chemokine receptors, where CXCR2 was the only receptor being activated. In addition, vCXCL1GT5 recruited β-arrestin in a BRET-based assay and induced migration in a chemotaxis assay through CXCR2, but not CXCR1. In contrast, vCXCL1GT1 stimulated G protein signaling, recruited β-arrestin and induced migration through both CXCR1 and CXCR2. Both vCXCL1GT1 and vCXCL1GT5 induced equally potent and efficacious migration of neutrophils, and ELR vCXCL1GT4 and non-ELR vCXCL1GT6 activated only CXCR2. In contrast to most human chemokines, the 14 UL146 genotypes have remarkably long C-termini. Comparative modeling using Rosetta showed that each genotype could adopt the classic chemokine core structure, and predicted that the extended C-terminal tail of several genotypes (including vCXCL1GT1, vCXCL1GT4, vCXCL1GT5, and vCXCL1GT6) forms a novel β-hairpin not found in human chemokines. Secondary NMR shift and TALOS+ analysis of vCXCL1GT1 supported the existence of two stable β-strands. C-terminal deletion of vCXCL1GT1 resulted in a non-functional protein and in a shift to solvent exposure for tryptophan residues likely due to destabilization of the chemokine fold. The results demonstrate that non-ELR chemokines can activate CXCR2 and suggest that the UL146 chemokines have unique C-terminal structures that stabilize the chemokine fold. Increased knowledge of the structure and interaction partners of the chemokine variants encoded by UL146 is key to understanding why circulating HCMV strains sustain 14 stable genotypes.
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Broxmeyer, Hal E. "Chemokines and chemokine receptors in hematopoiesis and immunology." Experimental Hematology 34, no. 8 (August 2006): 965–66. http://dx.doi.org/10.1016/j.exphem.2006.05.020.
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Meissner, Anja, Olaf Zilles, Rosa Varona, Katrin Jozefowski, Uwe Ritter, Gabriel Marquez, Rupert Hallmann, and Heinrich Körner. "CC chemokine ligand 20 partially controls adhesion of naive B cells to activated endothelial cells under shear stress." Blood 102, no. 8 (October 15, 2003): 2724–27. http://dx.doi.org/10.1182/blood-2003-01-0007.
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Abstract Chemokines are thought to control lymphocyte recruitment to the inflamed endothelium. To dissect chemokine-mediated adhesion, binding of ex vivo isolated splenocytes to tumor necrosis factor (TNF)–activated endothelial cells was analyzed under shear stress. We observed specific adhesion of naive follicular B cells, which could be blocked by pertussis toxin. This indicated a G protein–mediated binding and pointed at a contribution of chemokine receptors to B-cell adhesion. Analysis of chemokines expressed by TNF-activated endothelial cells showed that CC chemokine ligand 2 (CCL2), CCL17, and CCL20 were up-regulated. Only on follicular B cells was the cognate receptor for CCL20, CC chemokine receptor 6 (CCR6), expressed strongly, and a functional transmigration assay with CCR6-negative B cells demonstrated conclusively the sole signaling of CCL20 through CCR6. Desensitization of CCR6 on naive B cells with CCL20 resulted in receptor down-regulation and reduced B-cell adhesion. We conclude that CCL20 plays a vital role in B-cell adhesion to the inflamed endothelium.
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Höpken, Uta E., Hans-Dieter Foss, Dagmar Meyer, Michael Hinz, Korinna Leder, Harald Stein, and Martin Lipp. "Up-regulation of the chemokine receptor CCR7 in classical but not in lymphocyte-predominant Hodgkin disease correlates with distinct dissemination of neoplastic cells in lymphoid organs." Blood 99, no. 4 (February 15, 2002): 1109–16. http://dx.doi.org/10.1182/blood.v99.4.1109.
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Chemokines and chemokine receptors are key mediators for regulating cell traffic and positioning in both homeostatic and inflammatory conditions. It is also presumed that chemokines and their receptors are likely to play a critical role in the localization of malignant hematopoietic cells in their target organs. This study analyzed chemokine and chemokine receptor expression in several Hodgkin disease (HD)–derived cell lines and in HD tumors. All HD-derived cell lines expressed functional CCR7 and CXCR4 receptors. CCR7 up-regulation was mediated by constitutive NF-κB activity. Lymphoid tissues in HD revealed differential expression levels of CCR7, CXCR4, and CXCR5, depending on the distinct subtypes of HD. HD of the classical subtypes, predominantly located in the interfollicular zone, showed strong CCR7 and CXCR4 expression and moderate CXCR5 expression. In contrast, the nodular lymphocyte-predominant HD (NLP) subtype, regularly associated with follicular structures, exhibited no CCR7 reactivity but abundant CXCR4 staining. Their respective chemokine ligands showed marked expression by reactive cells within the tumors of classical HD and outside of the tumor nodules in NLPHD. Functionally, such differential chemokine receptor expression might contribute to specific localization and confinement of neoplastic cells within the target organs in the distinct HD entities.
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Blanchetot, Christophe, Dennis Verzijl, Azra Mujić-Delić, Leontien Bosch, Louise Rem, Rob Leurs, C. Theo Verrips, Michael Saunders, Hans de Haard, and Martine J. Smit. "Neutralizing Nanobodies Targeting Diverse Chemokines Effectively Inhibit Chemokine Function." Journal of Biological Chemistry 288, no. 35 (July 8, 2013): 25173–82. http://dx.doi.org/10.1074/jbc.m113.467969.
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Kiguchi, Norikazu, Fumihiro Saika, Yuka Kobayashi, and Shiroh Kishioka. "Epigenetic regulation of CC-chemokine ligand 2 in nonresolving inflammation." Biomolecular Concepts 5, no. 4 (August 1, 2014): 265–73. http://dx.doi.org/10.1515/bmc-2014-0022.
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AbstractInflammation mediated by the crosstalk between leukocytes and resident tissue cells is crucial for the maintenance of homeostasis. Because chemokine ligands and receptors, which recruit a variety of leukocytes, are widely distributed among tissues, it is important to understand the mechanisms regulating inflammatory disease. Chemokines such as CC-chemokine ligand 2 (CCL2) amplify and maintain inflammation through chemokine-cytokine networks after the recruitment of circulating leukocytes. Chemokine-dependent nonresolving inflammation occurs in the peripheral and central nervous systems, and underlies several intractable diseases, including cancer and neuropathic pain. The chronic upregulation of chemokines is often mediated by epigenetic mechanisms consisting of DNA methylation, histone modification, and nucleosome positioning. In particular, histone acetylation and methylation have been shown to play important roles in the upregulation of chemokine expression. In addition to CCL2, several other chemokines strongly contribute to neuropathic pain through epigenetic induction. Consequently, targeting epigenetic changes may have therapeutic potential for nonresolving inflammatory diseases such as neuropathic pain. Further research into the epigenetics of inflammatory diseases should promote the development of novel and effective treatment strategies for intractable inflammatory diseases.
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Stine, Johnny T., Christi Wood, Mark Hill, Angela Epp, Carol J. Raport, Vicki L. Schweickart, Yoshio Endo, et al. "KSHV-encoded CC chemokine vMIP-III is a CCR4 agonist, stimulates angiogenesis, and selectively chemoattracts TH2 cells." Blood 95, no. 4 (February 15, 2000): 1151–57. http://dx.doi.org/10.1182/blood.v95.4.1151.004k37_1151_1157.
Full textAbstract:
Kaposi's sarcoma-associated herpesvirus (KSHV) encodes 3 genes that are homologous to cellular chemokines. vMIP-III, the product of open reading frame K4.1, is the most distantly related to human chemokines and has yet to be characterized. We have examined the interaction of vMIP-III with chemokine receptors, its expression in KS lesions, and its in ovo angiogenic properties. We show expression of vMIP-III in KS lesions and demonstrate the stimulation of angiogenesis by this chemokine, like vMIP-I and vMIP-II, in the chick chorioallantoic membrane assay. vMIP-III does not block human immunodeficiency virus entry through the coreceptors CCR3, CCR5, or CXCR4. However, vMIP-III is an agonist for the cellular chemokine receptor CCR4. CCR4 is expressed by TH2-type T cells. Consistent with this, vMIP-III preferentially chemoattracts this cell type. Because of these biologic properties and because it is expressed in KS lesions, vMIP-III may play an important role in the pathobiology of KS.
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Lim, Herman D., J. Robert Lane, Meritxell Canals, and Martin J. Stone. "Systematic Assessment of Chemokine Signaling at Chemokine Receptors CCR4, CCR7 and CCR10." International Journal of Molecular Sciences 22, no. 8 (April 19, 2021): 4232. http://dx.doi.org/10.3390/ijms22084232.
Full textAbstract:
Chemokines interact with chemokine receptors in a promiscuous network, such that each receptor can be activated by multiple chemokines. Moreover, different chemokines have been reported to preferentially activate different signalling pathways via the same receptor, a phenomenon known as biased agonism. The human CC chemokine receptors (CCRs) CCR4, CCR7 and CCR10 play important roles in T cell trafficking and have been reported to display biased agonism. To systematically characterize these effects, we analysed G protein- and β-arrestin-mediated signal transduction resulting from stimulation of these receptors by each of their cognate chemokine ligands within the same cellular background. Although the chemokines did not elicit ligand-biased agonism, the three receptors exhibited different arrays of signaling outcomes. Stimulation of CCR4 by either CC chemokine ligand 17 (CCL17) or CCL22 induced β-arrestin recruitment but not G protein-mediated signaling, suggesting that CCR4 has the potential to act as a scavenger receptor. At CCR7, both CCL19 and CCL21 stimulated G protein signaling and β-arrestin recruitment, with CCL19 consistently displaying higher potency. At CCR10, CCL27 and CCL28(4-108) stimulated both G protein signaling and β-arrestin recruitment, whereas CCL28(1-108) was inactive, suggesting that CCL28(4-108) is the biologically relevant form of this chemokine. These comparisons emphasize the intrinsic abilities of different receptors to couple with different downstream signaling pathways. Comparison of these results with previous studies indicates that differential agonism at these receptors may be highly dependent on the cellular context.
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Fauriat, Cyril, Eric O. Long, Hans-Gustaf Ljunggren, and Yenan T. Bryceson. "Regulation of human NK-cell cytokine and chemokine production by target cell recognition." Blood 115, no. 11 (March 18, 2010): 2167–76. http://dx.doi.org/10.1182/blood-2009-08-238469.
Full textAbstract:
AbstractNatural killer (NK)–cell recognition of infected or neoplastic cells can induce cytotoxicity and cytokine secretion. So far, it has been difficult to assess the relative contribution of multiple NK-cell activation receptors to cytokine and chemokine production upon target cell recognition. Using Drosophila cells expressing ligands for the NK-cell receptors LFA-1, NKG2D, DNAM-1, 2B4, and CD16, we studied the minimal requirements for secretion by freshly isolated, human NK cells. Target cell stimulation induced secretion of predominately proinflammatory cytokines and chemokines. Release of chemokines MIP-1α, MIP-1β, and RANTES was induced within 1 hour of stimulation, whereas release of TNF-α and IFN-γ occurred later. Engagement of CD16, 2B4, or NKG2D sufficed for chemokine release, whereas induction of TNF-α and IFN-γ required engagement of additional receptors. Remarkably, our results revealed that, upon target cell recognition, CD56dim NK cells were more prominent cytokine and chemokine producers than CD56bright NK cells. The present data demonstrate how specific target cell ligands dictate qualitative and temporal aspects of NK-cell cytokine and chemokine responses. Conceptually, the results point to CD56dim NK cells as an important source of cytokines and chemokines upon recognition of aberrant cells, producing graded responses depending on the multiplicity of activating receptors engaged.