PubMed · 11586602
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E P Curry. Case study: personal and professional integrity.. https://pubmed.ncbi.nlm.nih.gov/11586602/
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Colorectal MSI tumors are associated with an increased immune response. On the other hand, immunodeficient patients are more prone to lymphomas with the MSI phenotype. These facts are of wide interest in understanding the complex link between immunity and cancer, particularly of the MSI phenotype. Specific attention to the host immune system should thus be considered in the treatment of patients with MSI tumors.
Regulation of cytokine and chemokine expression in microglia may have implications for CNS inflammatory disorders. In this study we examined the role of the cyclopentenone PG 15-deoxy-Delta(12,14)-PGJ(2) (15d-PGJ(2)) in microglial inflammatory activation in primary cultures of human fetal microglia. 15d-PGJ(2) potently inhibited the expression of microglial cytokines (IL-1, TNF-alpha, and IL-6). We found that 15d-PGJ(2) had differential effects on the expression of two alpha-chemokines; whereas the Glu-Lys-Arg (ELR)(-) chemokine IFN-inducible protein-10/CXCL10 was inhibited, the ELR(+) chemokine IL-8/CXCL8 was not inhibited. These findings were shown in primary human microglia and the human monocytic cells line THP-1 cells, using diverse cell stimuli such as bacterial endotoxin, proinflammatory cytokines (IL-1 and TNF-alpha), IFN-beta, and HIV-1. Furthermore, IL-8/CXCL8 expression was induced by 15d-PGJ(2) alone or in combination with TNF-alpha or HIV-1. Combined results from EMSA, Western blot analysis, and immunocytochemistry showed that 15d-PGJ(2) inhibited NF-kappaB, Stat1, and p38 MAPK activation in microglia. Adenoviral transduction of super-repressor IkappaBalpha, dominant negative MKK6, and dominant negative Ras demonstrated that NF-kappaB and p38 MAPK were involved in LPS-induced IFN-inducible protein 10/CXCL10 production. Interestingly, although LPS-induced IL-8/CXCL8 was dependent on NF-kappaB, the baseline or 15d-PGJ(2)-mediated IL-8/CXCL8 production was NF-kappaB independent. Our results demonstrate that 15d-PGJ(2) has opposing effects on the expression of two alpha-chemokines. These data may have implications for CNS inflammatory diseases.
Epidemiological studies have identified abuse of nitrite inhalants as an independent co-factor in HIV infection and in Kaposi's sarcoma (KS) in AIDS patients. In the present study we investigated the ability of macrophages from mice exposed to isobutyl nitrite to produce the inflammatory cytokine IL-1beta, upon stimulation with IFN-gamma and LPS. The production of IL-1beta was inhibited up to 55%. IL-1beta mRNA transcription was reduced by 35% following nitrite inhalant exposure, consistent with inhibition of activation-induced phosphorylation of macrophage mitogen-activated protein kinase p38. However, synthesis of the 31 kDa IL-1beta precursor protein was only marginally inhibited. Caspase-1, which cleaves the precursor IL-1beta into mature 17 kDa IL-1beta, was examined. Nitrite inhalant exposure blocked activation-induced increases in caspase-1 activity, consistent with a 50% reduction in 17 kDa IL-1beta shown in Western blots. Thus, exposure to nitrite inhalants reduced macrophage production of IL-1beta by reducing transcription, as well as post-translational processing mediated by caspase-1.