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

We investigated whether pertussis toxin (PT)-sensitive heterotrimeric Gi proteins (Gi1, Gi2, Gi3) are involved in the regulation of TCR-induced activation of human T cells. First, Gi proteins were inactivated by PT: pretreatment with PT of purified blood T lymphocytes before CD3 cross-linking inhibited cell proliferation (-71.1 +/- 22.0%, P < 0.001), production of interleukin-2 (IL-2; -47.3 +/- 12.6%, P = 0.008), and expression of CD25 (-24.6 +/- 11.7%, P < 0.001) and CD69 (-25.7 +/- 9.0%, P < 0.001). Then, to identify which of the three Gi was involved, Gi1, Gi2, and Gi3 proteins were specifically inactivated by stably transfecting dominant-negative mutated forms of their alpha subunit in Jurkat cells. After activation, IL-2 production and CD69 expression were inhibited only in cells expressing inactive Gi2. We then studied the effects of interleukin-8 (IL-8), a CXC-chemokine with receptors coupled to Gi2 and produced in an autocrine fashion by activated T cells. Although its effects varied among donors, exogenous IL-8 stimulated proliferation and CD25 expression (up to, respectively, 200 and 77%) of PB T lymphocytes in response to CD3 activation, in a PT-sensitive manner. IL-8 also stimulated IL-2 production (by up to 42%) and CD69 expression, although weakly (+27%). Anti-human IL-8 antibody inhibited proliferation (-43%) and CD25 up-regulation (-45%) of activated T lymphocytes. In summary, several major responses of human T lymphocytes to TCR-mediated activation are regulated by Gi2 proteins, which for this function can be activated by IL-8 in an autocrine manner.
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PMID:Positive regulation of human T cell activation by Gi2 proteins and interleukin-8. 1081 Oct 16

Chemokines are involved in the regulation of leukocyte migration and for some of them, T-cell costimulation. To date, the only direct property of lymphotactin (Lptn), the unique member of the C class of chemokines, consists of T-cell chemoattraction. This report describes a novel function for Lptn in human T-lymphocyte biology, by demonstrating the direct ability of Lptn to both inhibit and costimulate CD4(+) and CD8(+) T-cell activation, respectively. Lptn but not RANTES inhibited CD4(+) T-cell proliferation, through a decreased production of Th1 (interleukin [IL]-2, interferon [IFN]-gamma) but not Th2 (IL-4, IL-13) lymphokines, and decreased IL-2R alpha expression. Transfections in Jurkat cells showed a Lptn-mediated transcriptional down-regulation of gene-promoter activities specific for Th1-type lymphokines, as well as of nuclear factor of activated T cells (NF-AT) but not AP-1 or NF-KB enhancer activities. This suppressive action of Lptn could be compensated by overexpression of NF-ATc but not NF-ATp. CD4(+) T-cell proliferation was completely restored by exogenous IL-2 or reversed by pertussis toxin, wortmannin, and genistein, suggesting the involvement of multiple partners in Lptn signaling. In contrast to CD4(+) cells, Lptn exerted a potent costimulatory activity on CD8(+) T-cell proliferation and IL-2 secretion. These data provide important insights into the role of Lptn in differential regulation of normal human T-cell activation and its possible implication in immune response disorders. (Blood. 2000;96:420-428)
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PMID:The C-class chemokine, lymphotactin, impairs the induction of Th1-type lymphokines in human CD4(+) T cells. 1088 1

HIV infects and propagates into CD4+ T lymphocytes and macrophages, although many other cell types play an important role in virus spreading and pathogenesis. In addition to regulatory viral proteins, the cytokine network has early been implicated as a major controller of the plastic capacity of HIV to spread productively or rather remain silently integrated in the chromosomes of infected cells. The recent discovery of CCR5 and CXCR4 as essential entry co-receptors together with CD4 has highlighted a novel and potentially important step in the pharmacological hunt for more effective antiviral agents. In addition to regulate HIV expression and replication, several cytokines have demonstrated the capacity of up- or down-modulating chemokine receptors including CCR5 and CXCR4 with the consequence of influencing the susceptibility of T cells and macrophages to HIV infection. Pharmacological agents such as pertussis toxin B-oligomer have demonstrated HIV suppressive effects via non competitive binding of CCR5, whereas interferons or interleukin-16 (IL-16) can prevent post-entry steps in HIV expression. At the clinical level, several cytokines or their receptors are useful markers for monitoring disease progression and its consequence on the immune system. Cytokine-based therapy represents a realistic complementary approach to traditional antiretroviral therapy potentially capable of restoring important adaptive or innate immune functions ultimately curtailing HIV spreading and its consequences on the immune system, as exemplified by the experimental clinical use of IL-2.
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PMID:Cytokine and chemokine based control of HIV infection and replication. 1147 51

Previously, we have demonstrated age-associated alterations in transmembrane signaling. One of the most reproducible alterations found in the immune response with aging is the decrease of lymphocyte proliferation on stimulation with various different mitogens. Here, we confirm that proliferative responses to stimulation with phytohaemagglutin (PHA), recombinant human IL-2, or anti-CD3 monoclonal antibody are all greater in the young (20-25 years) than old (60-87 years) population. We attempted to modulate the proliferative response using various agents acting at different levels of transmembrane signaling (pertussis toxin, cholera toxin, isoproterenol, PMA, Ca ionophore A23187), as well as at the level of the lymphocyte plasma membrane (methyl-beta-cyclodextrin, MBCD), or by using antioxidant vitamins (Vitamin E or C). None of these agents was able to restore effectively the proliferative response of lymphocytes from the aged to the level of young subjects. Even the combination of A23187 and PMA acting directly on calcium metabolism and protein kinase C activity was insufficient to restore the decreased mitogenic capacity of T cells from elderly subjects. Cyclodextrin, which decreases the cholesterol content of the membrane, increased the proliferative response of lymphocytes of elderly subjects, but not to the level of the young. Vitamin E had a very strong inhibitory effect on lymphocyte stimulation in both the age groups, except in combination with MBCD in T cells of the elderly, while Vitamin C had no significant modulatory effect. MAPK ERK and p38 activation was found to be decreased with aging in T cells after anti-CD3 mAb stimulation. Vitamin E but not Vitamin C strongly inhibited MAPK ERK or p38 activation. The direct activation of certain molecules or the modulation of the cholesterol content of the membrane seems to be effective immunomodulatory interventions with aging.
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PMID:Modulation of human lymphocyte proliferative response with aging. 1177 24

Recently we found that CXCL12/SDF-1 is a costimulator of peripheral CD4+ T cells. In this study, we report that CXCL12 alone induced expression of activation markers by peripheral CD4+ memory T cells and costimulated activation marker expression by anti-CD3 stimulated peripheral CD4+ naive and CD4+ memory T cells as well as by peripheral CD8+ T cells. The stimulation by CXCL12 was inhibited by Pertussis Toxin (PTX), but not by anti-CD25 mAb. CXCL12 also induced enhancement of IL-2 production and proliferation by anti-CD3 stimulated CD4+ memory T cells, but not by CD4+ naive T cells. PTX inhibited the enhancement of IL-2 production and proliferation, whereas anti-CD25 mAb inhibited proliferation, but not IL-2 production. Thus, CXCL12 upregulated T-cell activation, and a G-coupled protein mediated signaling pathway was necessary for stimulation of T cells by CXCL12.
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PMID:Stimulation of T-Cell activation by CXCL12/stromal cell derived factor-1 involves a G-protein mediated signaling pathway. 1208 13

We provide evidence that platelet factor 4 (PF4), but not the related chemokine neutrophil-activating polypeptide-2, induced highly purified human natural killer (NK) cells to produce interleukin (IL)-8 in a time- and dosage-dependent manner. This ability was retained even while PF4 was bound to heparin. PF4 increased the steady state level of IL-8 mRNA, likely implying a transcriptional effect of PF4. Stimulation of NK cells through the Fc receptor for immunoglobulin G-IIIA was found to synergistically increase the effect of PF4 on IL-8 production but did not affect IL-2-related activities such as cytotoxic activity and proliferation. Pertussis toxin did not block the PF4-derived IL-8 production in NK cells, but this response was sensitive to wortmannin, implicating a role of phosphatidylinositol 3-kinase in the intracellular signaling pathway triggered by PF4. Our results characterize a new capacity for PF4 and provide further evidence for the pivotal role of NK cells in the environment of inflammation.
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PMID:Platelet factor 4 induces human natural killer cells to synthesize and release interleukin-8. 1222 28

T cells resistant to the immunosuppressive drug cyclosporin A (CsA) may be important mediators of chronic graft rejection. We previously reported that T cells activated in the presence of endothelial cells (EC) develop resistance to CsA, and initiate IL-2 secretion within 8-12 h of triggering. CsA normally blocks the phosphatase, calcineurin, thus preventing nuclear translocation of the transcription factor, NFAT. We find that in the presence but not the absence of EC, NFAT1 can be detected in the nuclei of CsA-treated T cells within 8 h of triggering, reaching a maximal level of 60% of control by 24 h. Glycogen synthase kinase-3beta (GSK-3beta), which rephosphorylates NFAT and promotes nuclear export, is inhibited by EC costimulation. GSK-3beta is a component of the wnt signaling pathway, and EC express wnt-5a and T cells express frizzled-5, a wnt-5a receptor. Wnt-5a promotes T cell NFAT nuclear accumulation in the presence of CsA, an effect mimicked by Li(+), a potent inhibitor of GSK-3beta. The protein kinase C agonist PMA dramatically synergizes with both EC and wnt-5a in stimulating T cell IL-2 synthesis, and inhibition of either protein kinase C by Ro-31-8425 or G-proteins by pertussis toxin effectively blocks the actions of wnt-5a on T cells. Finally, a secreted, dominant-negative form of frizzled-5 blocks EC-mediated CsA resistance. Thus, EC promote CsA-resistant nuclear localization of NFAT and subsequent IL-2 synthesis through a noncanonical wnt-dependent pathway.
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PMID:Endothelial cells stimulate T cell NFAT nuclear translocation in the presence of cyclosporin A: involvement of the wnt/glycogen synthase kinase-3 beta pathway. 1224 65

We previously reported that murine experimental allergic encephalomyelitis can be induced by an additional intraperitoneal and intracerebral (i.c.) restimulation in resistant B6 mice after standard immunization with myelin antigens in complete Freund's adjuvant and Bordetella pertussis coadjuvant. Neutrophils infiltrated into perivascular spaces at 12 h, followed by mononuclear cells 24 h after i.c. injection. In this study, we report that the i.c. injection induced the expression of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1). The kinetic expression of ICAM-1 or VCAM-1 on brain endothelial cells paralleled the infiltration of neutrophils and mononuclear cells, respectively. The infiltrated lymphocytes also expressed very late antigen-4 (VLA-4) molecules. The microvascular endothelial cells were positive for VCAM-1, whereas the surrounding mononuclear cells were VLA-4 positive. Furthermore, we found a unique subpopulation of cells with characteristics of CD4(-)CD8(-)V(beta)8(+) markers. The kinetic studies of this population showed that these cells were transiently depleted from 12 to 24 h after i.c. challenge (before the development of clinical symptoms) in cervical lymph nodes. These CD4(-)CD8(-)V(beta)8(+) cells can be expanded by in vitro culture with myelin basic protein or IL-2. No significant changes of CD4(+)/CD8(+) cells were noted. CD4(+)CD8(-)CD3(+) cells were also found in brain by double histochemical stains and were the major infiltrating cells at 24 or 48 h after i.c. challenge.
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PMID:Infiltrated Cells in Experimental Allergic Encephalomyelitis by Additional Intracerebral Injection in Myelin-Basic-Protein-SensitizedB6 Mice. 1238 77

Experimental autoimmune encephalomyelitis (EAE) is an animal model of human multiple sclerosis that requires the activation of autoreactive T cells for the expression of pathology. EAE has been most frequently studied in the Lewis rat model as well as in several murine models of EAE including the PLJ and B10PL strains. In the present study we describe a novel model of EAE induced in the Wistar rat strain by immunization with guinea pig spinal cord antigens and pertussis toxin (PT). T cell responses were induced to myelin basic protein. Autoreactive T cells could be totally blocked by the in vitro treatment with CTLA4Ig, a protein that blocks the costimulation of autoreactive T cells. The addition of IL-2 could reverse the inhibition seen in vitro with CTLA4Ig. The effects of inhibition of B7 costimulation were also examined by an analysis of cytokine responses and IL-2 receptor on T cells. CTLA4Ig treatment in vitro reduced the expression of IL-2 receptor on T cells, enhanced T cell apoptosis and decreased the synthesis of IL-2, IFN-gamma and TNF-alpha. CTLA4Ig treatment had no effect on IL-10 synthesis by T cells, a cytokine implicated in the functions of regulatory T cell subsets. Overall, our studies support the rationale of B7 blocking therapies as a potential treatment for models of multiple sclerosis. The induction of EAE in the Wistar rat provides yet another novel model in which to examine the regulation of T cell autoimmunity.
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PMID:Experimental autoimmune encephalomyelitis in the Wistar rat: dependence of MBP-specific T cell responsiveness on B7 costimulation. 1238 44

In this report we describe pertussis toxin-induced reversible encephalopathy dependent on monocyte chemoattractant protein-1 (MCP-1) overexpression (PREMO), a novel animal model that exhibits features of human encephalopathic complications of inflammatory disorders such as viral meningoencephalitis and Lyme neuroborreliosis as well as the mild toxic encephalopathy that commonly precedes relapses of multiple sclerosis (MS). Overexpression of the mouse MCP-1 gene product (classically termed JE) in astrocytes, the major physiological CNS cellular source of MCP-1, failed to induce neurological impairment. Unexpectedly, transgenic (tg) mice overexpressing MCP-1 at a high level (MCP-1(hi)) manifested transient, severe encephalopathy with high mortality after injections of pertussis toxin (PTx) plus complete Freund's adjuvant (CFA). Surviving mice showed markedly improved function and did not relapse during a prolonged period of observation. Tg mice that expressed lower levels of MCP-1 were affected minimally after CFA/PTx injections, and tg expression of other chemokines failed to elicit this disorder. The disorder was significantly milder in mice lacking T-cells, which therefore play a deleterious role in this encephalopathic process. Disruption of CC chemokine receptor 2 (CCR2) abolished both CNS inflammation and encephalopathy, identifying CCR2 as a relevant receptor for this disorder. Proinflammatory and type 1 cytokines including TNF-alpha, IL-1beta, IFN-gamma, IL-2, RANTES, and IP-10 were elevated in CNS tissues from mice with PREMO. These studies characterize a novel model of reversible inflammatory encephalopathy that is dependent on both genetic and environmental factors.
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PMID:Pertussis toxin-induced reversible encephalopathy dependent on monocyte chemoattractant protein-1 overexpression in mice. 1248 56


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