Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0037116 (silicosis)
 1,822 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Macrophages play a fundamental role in silicosis in part by removing silica particles and producing inflammatory mediators in response to silica. Tumor necrosis factor alpha (TNFalpha) is a prominent mediator in silicosis. Silica induction of apoptosis in macrophages might be mediated by TNFalpha. However, TNFalpha also activates signal transduction pathways (NF-kappaB and AP-1) that rescue cells from apoptosis. Therefore, we studied the TNFalpha-mediated mechanisms that confer macrophage protection against the pro-apoptotic effects of silica. We will show that exposure to silica induced TNFalpha production by RAW 264.7 cells, but not by IC-21. Silica-induced activation of NF-kappaB and AP-1 was only observed in RAW 264.7 macrophages. ERK activation in response to silica exposure was only observed in RAW 264.7 macrophages, whereas activation of p38 phosphorylation was predominantly observed in IC-21 macrophages. No changes in JNK activity were observed in either cell line in response to silica exposure. Silica induced apoptosis in both macrophage cell lines, but the induction of apoptosis was significantly larger in IC-21 cells. Protection against apoptosis in RAW 264.7 cells in response to silica was mediated by enhanced NF-kappaB activation and ERK-mediated phosphorylation of the p55 TNFalpha receptor. Inhibition of these two protective mechanisms by specific pharmacological inhibitors or transfection of dominant negative mutants that inhibit IkappaBalpha or ERK phosphorylation significantly increased silica-induced apoptosis in RAW 264.7 macrophages. These data suggest that NF-kappaB activation and ERK-mediated phosphorylation of the p55 TNF receptor are important cell survival mechanisms in the macrophage response to silica exposure.
 ...
PMID:Phosphorylation of tumor necrosis factor receptor 1 (p55) protects macrophages from silica-induced apoptosis. 1457 Aug 68

Plant alkaloid tetrandrine (Tet), purified from Chinese herb Han-Fang Chi, is a potent immunomodulator used to treat rheumatic disorders, silicosis and hypertension in mainland China. We previously demonstrated that Tet effectively suppresses cytokine production and proliferation of CD28-costimulated T cells. In the present study, we investigated the possible involvement of nuclear factor kappa B (NF-kappaB) transcription factors, critical in CD28 costimulation, in Tet-mediated immunosuppression in human peripheral blood T cells. We showed that Tet inhibited NF-kappaB DNA-binding activities induced by various stimuli, including CD28 costimulation. At equal molar concentrations, Tet was as strong as methotrexate in suppressing CD28-costimulated NF-kappaB activities. Since Tet itself did not affect NF-kappaB binding to its corresponding DNA sequence, the results suggested that Tet might regulate NF-kappaB upstream signaling molecules. Further studies demonstrated that Tet could prevent the degradation of IkappaBalpha and inhibit nuclear translocation of p65 by blocking IkappaBalpha kinases alpha and beta activities. In addition, the activation of mitogen-activated protein kinases such as c-jun N-terminal kinase, p38 and extracellular signal-regulated kinase and activator protein-1 DNA-binding activity were all downregulated by Tet. Transfection assays performed in purified human peripheral blood T cells also confirmed the inhibition of NF-kappaB transcriptional activity by Tet. When four Tet analogues were readily compared, dauricine appeared to preserve the most potent inhibition on CD28-costimulated but not on H(2)O(2)-induced NF-kappaB DNA-binding activities. Our results provide the molecular basis of immunomodulation of Tet for being a potential disease-modifying antirheumatic drug in the therapy of autoimmune disorders like rheumatoid arthritis.
 ...
PMID:Plant alkaloid tetrandrine downregulates IkappaBalpha kinases-IkappaBalpha-NF-kappaB signaling pathway in human peripheral blood T cell. 1550 55

Tetrandrine (TET) is the major pharmacologically active compound of Chinese herb Stephania tetrandra S Moore, which has been used traditionally for the treatment of rheumatic disorders, silicosis and hypertension. Concanavalin A (ConA)-induced hepatitis (CIH) is a T-cell-dependent hepatitis and a well-established animal model for studying the mechanisms and therapy of immune-mediated hepatotoxicity. The aim of this study was to investigate whether TET could protect mice from CIH. C57BL/6 mice were injected with ConA to induce CIH pretreated with or without TET. Liver injury was assessed biochemically and histologically. Levels of plasma cytokines and the expressions of chemokine messenger RNA (mRNA) in the liver were determined. We found that pretreatment of mice with TET markedly reduced plasma transaminase release and the severity of liver damage. We further investigated the mechanisms of the protective effects of TET. When CIH-induced mice pretreated with TET, the increases of plasma concentrations of TNF-alpha, IFN-gamma, IL-12 and IL-4 were dramatically attenuated; at the same time, IFN-inducible protein-10 and macrophage inflammatory protein-1alpha expressions in liver were decreased. Furthermore, TET inhibited NF-kappaB activity, the critical transcriptional factor of the above mentioned inflammatory cytokines, by preventing the activation of IkappaBalpha kinasealpha (IKKalpha) and then inhibiting phosphorylation of IkappaBalpha to stabilize IkappaBalpha in intrahepatic leukocytes. In conclusion, TET is able to prevent T-cell-mediated liver injury in vivo. The beneficial effect may depend on suppressing the production of various inflammatory mediators in the liver through inhibiting of NF-kappaB activation.
 ...
PMID:Tetrandrine protects mice from concanavalin A-induced hepatitis through inhibiting NF-kappaB activation. 1899 79