-
International Journal of Molecular... Oct 2020CC chemokines (or β-chemokines) are 28 chemotactic cytokines with an N-terminal CC domain that play an important role in immune system cells, such as CD4 and CD8... (Review)
Review
CC chemokines (or β-chemokines) are 28 chemotactic cytokines with an N-terminal CC domain that play an important role in immune system cells, such as CD4 and CD8 lymphocytes, dendritic cells, eosinophils, macrophages, monocytes, and NK cells, as well in neoplasia. In this review, we discuss human CC motif chemokine ligands: CCL1, CCL3, CCL4, CCL5, CCL18, CCL19, CCL20, CCL21, CCL25, CCL27, and CCL28 (CC motif chemokine receptor CCR5, CCR6, CCR7, CCR8, CCR9, and CCR10 ligands). We present their functioning in human physiology and in neoplasia, including their role in the proliferation, apoptosis resistance, drug resistance, migration, and invasion of cancer cells. We discuss the significance of chemokine receptors in organ-specific metastasis, as well as the influence of each chemokine on the recruitment of various cells to the tumor niche, such as cancer-associated fibroblasts (CAF), Kupffer cells, myeloid-derived suppressor cells (MDSC), osteoclasts, tumor-associated macrophages (TAM), tumor-infiltrating lymphocytes (TIL), and regulatory T cells (T). Finally, we show how the effect of the chemokines on vascular endothelial cells and lymphatic endothelial cells leads to angiogenesis and lymphangiogenesis.
Topics: Animals; Cell Proliferation; Chemokines, CC; Humans; Neoplasms; Receptors, CCR; Signal Transduction; Tumor Microenvironment
PubMed: 33076281
DOI: 10.3390/ijms21207619 -
AIDS Research and Human Retroviruses Jun 1998A small revolution has occurred in the field of AIDS research. A number of chemokines, most of which belong to the CC or beta family, were found by us and others to... (Review)
Review
A small revolution has occurred in the field of AIDS research. A number of chemokines, most of which belong to the CC or beta family, were found by us and others to inhibit HIV infection potently and specifically. The mechanism of such inhibition was shown to be at the level of receptor binding, as these chemokines are binding to receptors that mediate HIV infection. Therefore, chemokines effectively block entry of HIV. Although chemokines have a natural function as chemoattractants, it is intriguing to think that in crossing their path with the virus, they constitute the first example of a naturally occurring soluble molecule, other than antibodies, that can specifically prevent infection. Thus, chemokines could play a role in protective immunity against HIV infection together with other classic correlates, such as neutralizing antibodies and cytotoxic T cells, and some clinical studies suggest that this is indeed the case. Here we review and analyze some of the basic and clinical science that led to the elucidation of the role of chemokines and their receptor in protection from HIV infection.
Topics: Animals; CD8-Positive T-Lymphocytes; Chemokines, CC; Disease Progression; HIV Infections; HIV-1; Humans; Receptors, Chemokine; Solubility
PubMed: 9672236
DOI: No ID Found -
Immunological Reviews Jun 2007Chemokines have a clearly defined role in mobilizing the recruitment of leukocytes to both healthy and inflamed tissues. This review details work from our and other... (Review)
Review
Chemokines have a clearly defined role in mobilizing the recruitment of leukocytes to both healthy and inflamed tissues. This review details work from our and other laboratories, indicating that beta-chemokines may play important roles (i) in driving the terminal differentiation of mast cell precursors in mucosal tissues and (ii) in providing priming or costimulatory signals required for mast cell activation, leading to an antigen-driven inflammatory response. These data stem from in vivo, ex vivo, and in vitro studies. Data are also presented that suggest that Fc epsilon RI:chemokine receptor cross talk may involve spatiotemporal dynamics that may control the strength and nature of the complex activating signals controlling mast cell effector function.
Topics: Animals; Cell Membrane; Chemokines, CC; Conjunctiva; Humans; Hypersensitivity; Mast Cells; Receptors, IgE
PubMed: 17498054
DOI: 10.1111/j.1600-065X.2007.00521.x -
Journal of Neurovirology Feb 1999It has been speculated that beta-chemokines play a pivotal role in the development of peripheral nervous system (PNS) disorders characterized by mononuclear cell... (Review)
Review
It has been speculated that beta-chemokines play a pivotal role in the development of peripheral nervous system (PNS) disorders characterized by mononuclear cell infiltration. In experimental allergic neuritis (EAN), an animal model for human Guillain-Barré syndrome (GBS) with mononuclear cell infiltration, we found by quantitative PCR that beta-chemokine messages were upregulated during the active stage. Moreover, an increase in the monocyte chemoattractant protein-1 (MCP-1) message was found in the preclinical stage of EAN, suggesting the critical role of MCP-1 for inducing mononuclear cell infiltrations in this model. Since many cell lineages other than immune cells can produce chemokines, this early upregulation of MCP-1 may be mediated by non-immune cells, probably endothelia or Schwann cells. To date, apart from MCP-1, only RANTES (Regulated on activation, normal T cell expressed and secreted) and macrophage inflammatory protein (MIP)-1alpha have been examined in EAN and found to have similar kinetics of induction. Therefore, understanding the regulation of production of these chemokines as well as mechanisms of inhibiting chemokine/receptor interactions in the PNS may ultimately lead to disease-specific therapy for GBS and related demyelinating disorders.
Topics: Animals; Chemokine CCL2; Chemokines; Chemokines, CC; Demyelinating Diseases; Disease Models, Animal; Female; Humans; Neuritis, Autoimmune, Experimental; Peripheral Nervous System Diseases; Polyradiculoneuropathy; RNA, Messenger; Rats; Rats, Inbred Lew; Schwann Cells; Time Factors; Up-Regulation
PubMed: 10190687
DOI: 10.3109/13550289909029742 -
Journal of Leukocyte Biology May 1995Structural analysis of chemokines has revealed that the alpha/beta structural-fold is highly conserved among both the CXC and CC chemokine classes. Although dimerization... (Comparative Study)
Comparative Study Review
Structural analysis of chemokines has revealed that the alpha/beta structural-fold is highly conserved among both the CXC and CC chemokine classes. Although dimerization and aggregation is often observed, the chemokines function as monomers. The critical receptor binding regions are in the NH2-terminal 20 residues of the protein and are the least ordered in solution. The flexible NH2-terminal region is the most critical receptor binding site and a second site also exists in the loop that follows the two disulfides. The well-ordered regions are not directly involved in receptor binding but, along with the disulfides, they provide a scaffold that determines the conformation of the sites that are critical for receptor binding. These general requirements for function are common to all the chemokines. For the CC chemokines, receptor activation and receptor binding regions are separate within the 10 residue NH2-terminal region. This has allowed identification of high affinity analogs that do not activate the receptor and are potent antagonists.
Topics: Amino Acid Sequence; Animals; Chemokine CCL2; Chemokine CCL7; Chemokine CCL8; Chemokine CXCL1; Chemokines, CXC; Chemotactic Factors; Cytokines; Disulfides; Growth Substances; Humans; Intercellular Signaling Peptides and Proteins; Interleukin-8; Ligands; Molecular Sequence Data; Monocyte Chemoattractant Proteins; Protein Binding; Protein Structure, Tertiary; Receptors, Growth Factor; Sequence Alignment; Sequence Homology, Amino Acid; Structure-Activity Relationship
PubMed: 7759949
DOI: 10.1002/jlb.57.5.703 -
European Journal of Immunology Jul 2000The present study investigates the role of the HIV-suppressive beta-chemokines macrophage inflammatory protein (MIP)-1alpha, MIP-1 and RANTES in activation-induced cell...
The present study investigates the role of the HIV-suppressive beta-chemokines macrophage inflammatory protein (MIP)-1alpha, MIP-1 and RANTES in activation-induced cell death (AICD). A pool of these beta-chemokines reduced anti-CD3-induced apoptosis of T cell blasts from healthy blood donors in a dose-dependent manner. Although the pooled beta-chemokines were more effective, the inhibitory effect could also be mediated by each of the individual chemokines and was blocked by neutralizing anti-chemokine antibodies. The beta-chemokines also inhibited pokeweed mitogen/staphylococcal enterotoxin B-induced T lymphocyte apoptosis in 33/49 HIV-infected (HIV+) individuals. This anti-apoptotic effect was not correlated with the patients' CD4 T cell counts. beta-chemokines did not lead to altered secretion of IL-2, IL-4, IFN-gamma or IL-10 in response to activation stimuli in either normal T cell blasts or peripheral blood mononuclear cells from HIV+ individuals. Co-incubation with beta-chemokines did not inhibit anti-CD3-induced expression of cell surface Fas ligand, nor did it alter levels of the death receptor Fas or Bcl-2 in T cell blasts, suggesting that the beta-chemokines are blocking AICD downstream of Fas. These observations indicate that beta-chemokines may play a novel role as modulators of AICD, in addition to their known role as chemoattractants and inhibitors of HIV replication.
Topics: Antigens, CD; Antigens, Differentiation, T-Lymphocyte; Apoptosis; CD3 Complex; Cells, Cultured; Chemokine CCL3; Chemokine CCL4; Chemokine CCL5; Chemokines, CC; Enterotoxins; Fas Ligand Protein; HIV Infections; Humans; Interferon-gamma; Interleukin-10; Interleukin-2; Interleukin-4; Lectins, C-Type; Lymphocyte Activation; Macrophage Inflammatory Proteins; Membrane Glycoproteins; Pokeweed Mitogens; Proto-Oncogene Proteins c-bcl-2; Staphylococcus aureus; T-Lymphocytes; fas Receptor
PubMed: 10940894
DOI: 10.1002/1521-4141(200007)30:7<2048::AID-IMMU2048>3.0.CO;2-I -
Infection and Immunity Apr 2002Chemokines (CK) are potent leukocyte activators and chemoattractants and aid in granuloma formation, functions critical for the immune response to Mycobacterium...
Chemokines (CK) are potent leukocyte activators and chemoattractants and aid in granuloma formation, functions critical for the immune response to Mycobacterium tuberculosis. We hypothesized that infection of alveolar macrophages (AM) with different strains of M. tuberculosis elicits distinct profiles of CK, which could be altered by human immunodeficiency virus (HIV) infection. RANTES, macrophage inflammatory protein-1 alpha (MIP-1 alpha), and MIP-1 beta were the major beta-CK produced in response to M. tuberculosis infection. Virulent M. tuberculosis (H37Rv) induced significantly less MIP-1 alpha than did the avirulent strain (H37Ra), while MIP-1 beta and RANTES production was comparable for both strains. MIP-1 alpha and MIP-1 beta were induced by the membrane, but not cytosolic, fraction of M. tuberculosis. M. tuberculosis-induced CK secretion was partly dependent on tumor necrosis factor alpha (TNF-alpha). AM from HIV-infected individuals produced less TNF-alpha and MIP-1 beta than did normal AM in response to either M. tuberculosis strain. We tested the functional significance of decreased beta-CK secretion by examining the ability of beta-CK to suppress intracellular growth of M. tuberculosis. MIP-1 beta and RANTES suppressed intracellular growth of M. tuberculosis two- to threefold, a novel finding. Thus, beta-CK contribute to the innate immune response to M. tuberculosis infection, and their diminution may promote the intracellular survival of M. tuberculosis.
Topics: Chemokine CCL4; Chemokine CCL5; Chemokines, CC; Humans; Macrophage Inflammatory Proteins; Macrophages, Alveolar; Mycobacterium tuberculosis; Tumor Necrosis Factor-alpha
PubMed: 11895930
DOI: 10.1128/IAI.70.4.1684-1693.2002 -
Infection and Immunity Sep 1999In the present study, we describe the ability of Trypanosoma cruzi trypomastigotes to stimulate the synthesis of beta-chemokines by macrophages. In vivo infection with...
In the present study, we describe the ability of Trypanosoma cruzi trypomastigotes to stimulate the synthesis of beta-chemokines by macrophages. In vivo infection with T. cruzi led to MIP-1alpha, RANTES, and JE/MCP1 mRNA expression by cells from peritoneal inflammatory exudate. In addition, in vitro infection with T. cruzi resulted in expression of beta-chemokine MIP-1alpha, MIP-1beta, RANTES, and JE mRNA by macrophages. The expression of the beta-chemokine MIP-1alpha, MIP-1beta, RANTES, and JE proteins by murine macrophages cultured with trypomastigote forms of T. cruzi was confirmed by immunocytochemistry. Interestingly, macrophage infection with T. cruzi also resulted in NO production, which we found to be mediated mainly by beta-chemokines. Hence, treatment with anti-beta-chemokine-specific neutralizing antibodies partially inhibited NO release by macrophages incubated with T. cruzi parasites. Further, the addition of the exogenous beta-chemokines MIP-1alpha, MIP-1beta, RANTES, and JE/MCP-1 induced an increased T. cruzi uptake, leading to enhanced NO production and control of parasite replication in a dose-dependent manner. L-NMMA, a specific inhibitor of the L-arginine-NO pathway, caused a decrease in NO production and parasite killing when added to cultures of macrophages stimulated with beta-chemokines. Among the beta-chemokines tested, JE was more potent in inhibiting parasite growth, although it was much less efficient than gamma interferon (IFN-gamma). Nevertheless, JE potentiates parasite killing by macrophages incubated with low doses of IFN-gamma. Together, these results suggest that in addition to their chemotactic activity, murine beta-chemokines may also contribute to enhancing parasite uptake and promoting control of parasite replication in macrophages and may play a role in resistance to T. cruzi infection.
Topics: Animals; Cells, Cultured; Chemokine CCL2; Chemokine CCL3; Chemokine CCL4; Chemokine CCL5; Chemokines, CC; Female; Macrophage Activation; Macrophage Inflammatory Proteins; Macrophages; Mice; Mice, Inbred C3H; Nitric Oxide; Trypanosoma cruzi
PubMed: 10456936
DOI: 10.1128/IAI.67.9.4819-4826.1999 -
Cytokine Jul 2005Matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs), beta-chemokines, increased oxidative stress (SOX) and inflammation have been implicated as...
Matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs), beta-chemokines, increased oxidative stress (SOX) and inflammation have been implicated as important factors in atherosclerosis and vascular remodeling. We hypothesized the possible roles of beta-chemokines [monocyte chemoattractant protein-1 (MCP-1), macrophage inflammatory proteins (MIP-1alpha, MIP-1beta) and regulated upon activation, normal T-cell expressed and secreted (RANTES)] as regulators of the metabolism of the vascular extracellular matrix in conditions of increased SOX in hemodialysis (HD) patients. We compared pre-dialysis levels of MMP-9/TIMP-1 system, beta-chemokines, Cu/Zn superoxide dismutase (Cu/Zn SOD) as a marker of SOX and C-reactive protein (CRP) as a marker of inflammation in HD patients with and without cardiovascular disease (CVD) to those of controls. HD patients, particularly those with CVD, showed a significant increase in values of Cu/Zn SOD, CRP, TIMP-1, TIMP-1/MMP-9 ratio, MCP-1 and MIP-1beta, whereas RANTES levels were lower than in the controls. The levels of MIP-1alpha as well as MMP-9 in all HD groups were similar to the controls. The positive correlations were observed between the MMP-9/TIMP-1 system and beta-chemokines, SOX and inflammation in whole HD group and in the subgroup with CVD. Multivariate analysis showed that the duration of dialysis followed by Cu/Zn SOD, MIP-1alpha and beta levels were the significant positive predictors of TIMP-1. In conclusion, our data show that MMP-9/TIMP-1 system and beta-chemokines could cooperate in conditions of elevated SOX, which ultimately predisposes hemodialysis patients to accelerated atherosclerosis.
Topics: C-Reactive Protein; Cardiovascular Diseases; Chemokines, CC; Female; Humans; Male; Matrix Metalloproteinase 9; Middle Aged; Oxidative Stress; Renal Dialysis; Superoxide Dismutase; Tissue Inhibitor of Metalloproteinase-1
PubMed: 15896974
DOI: 10.1016/j.cyto.2004.12.020 -
Current Opinion in Rheumatology Nov 2003The triad of pathologic changes that defines systemic sclerosis (scleroderma) includes immune system activation with autoimmunity; an obliterative, proliferative small... (Review)
Review
PURPOSE OF REVIEW
The triad of pathologic changes that defines systemic sclerosis (scleroderma) includes immune system activation with autoimmunity; an obliterative, proliferative small vessel vasculopathy; and fibrosis. Available data suggest that several cytokines, including chemokines, contribute to the development of scleroderma complications. This review focuses on chemokines and their contribution to tissue fibrosis and pulmonary hypertension in scleroderma.
RECENT FINDINGS
Proteins and mRNAs for monocyte chemoattractant protein-1; pulmonary and activation-regulated chemokine; macrophage inflammatory protein-1, regulated upon activation normal T cell expressed and secreted; interleukin-8; and transforming growth factor-beta have been found in increased amounts in blood or involved tissue from scleroderma patients. These factors are likely to contribute directly to tissue damage in scleroderma through several pathways, including stimulation of extracellular matrix production, induction of TGF-beta production and activation, and chemoattraction of T cells and nonspecific inflammatory cells into tissues.
SUMMARY
Multiple chemokines are part of the pathologic network that causes tissue damage in scleroderma, and, as such, may provide therapeutic targets in scleroderma.
Topics: Animals; Biomarkers; Bronchoalveolar Lavage Fluid; Chemokine CCL2; Chemokine CCL5; Chemokines; Chemokines, CC; Female; Humans; Interleukin-8; Male; Scleroderma, Systemic; Sensitivity and Specificity; Severity of Illness Index; T-Lymphocytes; Transforming Growth Factor beta
PubMed: 14569209
DOI: 10.1097/00002281-200311000-00015