Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0043167 (pertussis)
 19,595 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Monocyte chemoattractant protein-1 (MCP-1) is a CC chemokine that attracts monocytes and T lymphocytes. Its receptor (CCR2) is a heptahelical G-protein-coupled receptor (GPCR) whose signal transduction pathways for chemotaxis have not been completely defined. Because other GPCRs stimulate the mitogen-activated protein kinase (MAPK) cascade, we examined this pathway's activity in response to MCP-1. MCP-1 induced rapid and transient activation of MAPK in human monocytes and in Chinese hamster ovary cells expressing CCR2B. This effect was largely insensitive to pertussis toxin and wortmannin, and was protein kinase C-dependent and protein tyrosine kinase-independent. PD 098059, an inhibitor of MEK activation, not only prevented MAPK activation but also inhibited MCP-1-induced chemotaxis. Because pertussis toxin and wortmannin also efficiently inhibit chemotaxis but do not completely inhibit MAPK activation, these data may define non-overlapping signal transduction pathways that all must be activated to produce chemokine-mediated chemotaxis.
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PMID:MCP-1-mediated chemotaxis requires activation of non-overlapping signal transduction pathways. 910 41

Monocyte chemoattractant protein-1 (MCP-1) is a C-C chemokine thought to play a major role in recruiting monocytes to the atherosclerotic plaque. Tissue factor (TF), the initiator of coagulation, is found in the atherosclerotic plaque, macrophages, and human aortic smooth muscle cells (SMC). The exposure of TF during plaque rupture likely induces acute thrombosis, leading to myocardial infarction and stroke. This report demonstrates that MCP-1 induces the accumulation of TF mRNA and protein in SMC and in THP-1 myelomonocytic leukemia cells. MCP-1 also induces TF activity on the surface of human SMC. The induction of TF by MCP-1 in SMC is inhibited by pertussis toxin, suggesting that the SMC MCP-1 receptor is coupled to a Gi-protein. Chelation of intracellular calcium and inhibition of protein kinase C block the induction of TF by MCP-1, suggesting that in SMC it is mediated by activation of phospholipase C. SMC bind MCP-1 with a Kd similar to that previously reported for macrophages. However, mRNA encoding the macrophage MCP-1 receptors, CCR2A and B, is not present in SMC, indicating that they possess a distinct MCP-1 receptor. These data suggest that in addition to being a chemoattractant, MCP-1 may have a procoagulant function and raise the possibility of an autocrine pathway in which MCP-1, secreted by SMC and macrophages, induces TF activity in these same cells.
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PMID:Tissue factor is induced by monocyte chemoattractant protein-1 in human aortic smooth muscle and THP-1 cells. 935 21

Trichosanthin (TCS), an active protein component isolated from a traditional Chinese medicinal herb Trichosanthes kirilowii, has been shown to inhibit HIV infection and has been applied in clinical treatment of AIDS. The recent development that chemokines and chemokine receptors play important roles in HIV infection led us to investigate the possible functional interaction of TCS with chemokines and their receptors. This study demonstrated that TCS greatly enhanced both RANTES (regulated upon activation, normal T cell expressed and secreted)- and stromal cell-derived factor (SDF)-1 alpha-stimulated chemotaxis (EC50 approximately equal to 1 nM) in leukocytes (THP-1, Jurkat, and peripheral blood lymphocyte cells) and activation of pertussis toxin-sensitive G proteins (EC50 approximately equal to 20 nM). TCS also significantly augmented chemokine-stimulated activation of chemokine receptors CCR5 and CXCR4 as well as CCR1, CCR2B, CCR3, and CCR4 transiently expressed in HEK293 cells. A mutant TCS with 4,000-fold lower ribosome-inactivating activity showed similar augmentation activity as wild-type TCS. Moreover, flow cytometry demonstrated that the specific association of TCS to the cell membranes required the presence of chemokine receptors, and laser confocal microscopy reveals that TCS was colocalized with chemokine receptors on the membranes. The results from TCS-Sepharose pull-down and TCS and chemokine receptor coimmunoprecipitation and cross-linking experiments demonstrated association of TCS with CCR5. Thus, our data clearly demonstrated that TCS synergizes activities of chemokines to stimulate chemotaxis and G protein activation, and the effects of TCS are likely to be mediated through its interaction with chemokine receptors.
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PMID:Anti-HIV agent trichosanthin enhances the capabilities of chemokines to stimulate chemotaxis and G protein activation, and this is mediated through interaction of trichosanthin and chemokine receptors. 1042 74

The monocyte chemotactic protein-1 (MCP-1) receptor (MCP-1R) is expressed on monocytes, a subpopulation of memory T lymphocytes, and basophils. Two alternatively spliced forms of MCP-1R, CCR2A and CCR2B, exist and differ only in their carboxyl-terminal tails. To determine whether CCR2A and CCR2B receptors function similarly, Jurkat T cells were stably transfected with plasmids encoding the human CCR2A or CCR2B gene. Nanomolar concentrations of MCP-1 induced chemotaxis in the CCR2B transfectants that express high, intermediate, and low levels of MCP-1R. Peak chemotactic activity was shifted to the right as receptor number decreased. Five-fold more MCP-1 was required to initiate chemotaxis of the CCR2A low transfectant, but the peak of chemotaxis was similar for the CCR2A and CCR2B transfectants expressing similar numbers of receptors. MCP-1-induced chemotaxis was sensitive to pertussis toxin, implying that both CCR2A and CCR2B are G(i)alpha protein coupled. MCP-1 induced a transient Ca(2+) flux in the CCR2B transfectant that was partially sensitive to pertussis toxin. In contrast, MCP-1 did not induce Ca(2+) flux in the CCR2A transfectant. Since MCP-1 can stimulate chemotaxis of the CCR2A transfectant without inducing Ca(2+) mobilization, Ca(2+) flux may not be required for MCP-1-induced chemotaxis in the Jurkat transfectants. These results indicate that functional differences exist between the CCR2A and CCR2B transfectants that can be attributed solely to differences in the carboxyl-terminal tail.
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PMID:Functional differences between monocyte chemotactic protein-1 receptor A and monocyte chemotactic protein-1 receptor B expressed in a Jurkat T cell. 1104 12

Monocyte chemoattractant protein-1 (MCP-1) induces monocyte chemotaxis via interaction with the MCP-1 receptor CCR2. We found that MCP-1 binding to monocytic THP-1 cells was increased by pre-treatment with MCP-1. The amount of CCR2 mRNA and the cell-surface expression of CCR2 were not affected by MCP-1 stimuli. In contrast, the MCP-1-treated THP-1 cells showed a sixfold increase in MCP-1 binding affinity compared with untreated cells. MCP-1 binding to CCR2B-transfected HEK-293 cells was also enhanced by pre-treatment with MCP-1, and MCP-1 binding affinity increased by sixfold. In both cell lines, the enhancement of MCP-1 binding by stimulation with MCP-1 was blocked by cytochalasin D, an inhibitor of actin polymerization. This effect of pre-treatment with MCP-1 is insensitive to pertussis toxin and partially blocked by U73122, an inhibitor of phospholipase C. These results demonstrate that the MCP-1 receptor binding affinity is up-regulated by MCP-1 stimuli in an actin polymerization-dependent manner.
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PMID:MCP-1 receptor binding affinity is up-regulated by pre-stimulation with MCP-1 in an actin polymerization-dependent manner. 1131 Aug 55

In a reconstituted flow chamber system, preincubation with chemokines can trigger the arrest of rolling monocytes, suggesting that this interaction could help recruit these cells to early atherosclerotic lesions. To date, however, the contribution of endothelium-derived chemokines found in these lesion to monocyte arrests has not been investigated. The endothelium of lesion-prone carotid arteries from apolipoprotein E-deficient (ApoE(-/-)) mice, but not control mice, presents the chemokines KC (mouse GRO-alpha) and JE (mouse monocyte chemoattractant protein-1 [MCP-1]). Arrest of a monocytic cell line or mouse blood monocytes perfused through carotid arteries of ApoE(-/-) mice was reduced by treating with either pertussis toxin, an antagonist of CXCR2, or an antibody to KC, but this process was insensitive to agents that blocked CCR-2 or JE. Conversely, monocyte accumulation more than doubled upon pre-perfusion of the carotid artery with KC but not with mouse MCP-1. Blockade of alpha(4)beta(1) integrin (VLA-4) or vascular cell adhesion molecule-1, but not CD18 or intercellular adhesion molecule-1, almost completely inhibited the arrest of monocytes. We conclude that when presented by early atherosclerotic lesions, KC but not murine MCP-1 triggers VLA-4-dependent monocyte recruitment.
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PMID:The chemokine KC, but not monocyte chemoattractant protein-1, triggers monocyte arrest on early atherosclerotic endothelium. 1169 68

A considerable fraction of tumor-associated macrophages (TAM) is located in the fibroblast-rich stromal compartment of desmoplastic breast carcinoma. We analyzed the migratory activity of blood monocytes (MO), the precursor cells of TAM, into 3-D cultures of carcinoma cells and fibroblasts from breast tumor origin. MO migration into breast tumor spheroids was highly variable: Hs578T spheroids showed high MO infiltration rates, T47D cultures were intermediate, whereas BT549, BT474 and MCF-7 spheroids were poorly infiltrated. MO infiltration was also high in tumor-derived fibroblast spheroids; however, no MO subpopulation with specific infiltrative potential was identified by CD14/CD16 expression profile. The infiltration of MO could be inhibited by pre-exposure to pertussis and cholera toxins, but only pertussis toxin, which blocks G(i) protein function, entirely inhibited MO migration. The G(i) coupled CCL2 receptor CCR2A/2B was expressed on roughly all MO. Furthermore, highly infiltrated tumor-derived fibroblast and Hs578T spheroids secreted considerable amounts of CCL2. In line with this, the infiltration of MO into fibroblast spheroids was suppressed by either addition of recombinant CCL2 to disturb the CCL2 gradient or by pre-incubation of MO with a CCR2A/2B blocking antibody. MO infiltration of Hs578T spheroids, however, could not be inhibited by CCL2 receptor blockade. Our study clearly shows that the CCL2-CCR2A/2B pathway is crucial for the recruitment of blood MO into tumor fibroblastic areas, whereas additional factors may be relevant for the migration of MO into tumor cell sites.
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PMID:Importance of CCL2-CCR2A/2B signaling for monocyte migration into spheroids of breast cancer-derived fibroblasts. 2060 53

Cytokine-like 1 (CYTL1) is a novel potential cytokine that was first identified in CD34(+) cells derived from bone marrow and cord blood, and it was also found using our immunogenomics strategy. The immunobiological functions of CYTL1 remain largely unknown, and its potential receptor(s) has not been identified. A previous proposed hypothesis suggested that CYTL1 had structural similarities with CCL2 and that CCR2 was a potential receptor of CYTL1. In this study, we verify that CYTL1 possesses chemotactic activity and demonstrate that its functional receptor is CCR2B using a series of experiments performed in HEK293 cells expressing CCR2B or CCR2B-EGFP, including chemotaxis, receptor internalization, and radioactive binding assays. CYTL1 chemoattracts human monocytes but not PBLs, and its chemotactic activity toward monocytes is dependent on the CCR2B-ERK pathway. Furthermore, both human and mouse recombinant CYTL1 protein have chemotactic effects on macrophages from wild-type mice but not from Ccr2(-/-) mice. Furthermore, the chemotactic activity of CYTL1 is sensitive to pertussis toxin. All of the above data confirm that CCR2B is a functional receptor of CYTL1.
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PMID:Cytokine-like 1 Chemoattracts Monocytes/Macrophages via CCR2. 2708 2