The Journal of immunology : official journal of the American Association of Immunologists
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Sepsis is still a major cause of mortality in the intensive critical care unit and results from an overwhelming immune response to the infection. TNF signaling pathway plays a central role in the activation of innate immunity in response to pathogens. Using a model of polymicrobial sepsis by i.p. injection of cecal microflora, we demonstrate a critical role of TNFR1 and R2 activation in the deregulated immune responses and death associated with sepsis. ⋯ Furthermore, using TNFR1/R2-deficient mice, TNF was found to be responsible for a decrease in CXCR2 expression, explaining reduced neutrophil extravasation and migration to the infectious site, and in neutrophil apoptosis. In line with the clinical experience, administration of Enbrel, a TNF-neutralizing protein, induced however only a partial protection in B6 mice, with no improvement of clinical settings, suggesting that future TNF immunomodulatory strategies should target TNFR1 and R2. In conclusion, the present data suggest that the endogenous TNFR1/R2 signaling pathway in polymicrobial sepsis reduces neutrophil recruitment contributing to mortality and as opposed to pan-TNF blockade is an important therapeutic target for the treatment of polymicrobial sepsis.
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IL-6 is a biological marker of ventilator-associated lung injury that may contribute to alveolar barrier dysfunction in acute respiratory distress syndrome. To determine whether IL-6 affects alveolar barrier disruption in a model of ventilator-induced lung injury, we examined alveolar barrier albumin flux in wild-type (WT) mice given an IL-6-blocking Ab (IL6AB) and mice deficient in IL-6 (IL6KO). Albumin flux was significantly higher in mice given IL6AB compared with mice given a control Ab. ⋯ IL6KO neutrophils were more adherent in an in vitro assay compared with WT neutrophils. IL-6 from a hematopoietic cell source limits alveolar barrier disruption potentially by reducing neutrophil contact with the endothelium. Modulation of IL-6 signaling in a cell type-specific fashion may be a therapeutic target for patients with acute lung injury.
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Mycobacterium tuberculosis (M. tb) must cause lung disease to spread. Matrix metalloproteinases (MMPs) degrade the extracellular matrix and are implicated in tuberculosis-driven tissue destruction. We investigated signaling pathways regulating macrophage MMP-1 and -7 in human pulmonary tuberculosis and examine the hypothesis that the antimycobacterial drug p-aminosalicylic acid acts by inhibiting such pathways. ⋯ In vitro, M. tb drives p38 phosphorylation. p38 inhibition suppresses M. tb-dependent MMP-1 secretion by 57.8% and concurrently increases secretion of its specific inhibitor TIMP-1 by 243.7%, demonstrating that p38 activity regulates matrix degradation by macrophages. p38 signals downstream to the cyclooxygenase 2/PGE(2) pathway. p-Aminosalicyclic acid, an agent used to treat drug-resistant tuberculosis, inhibits M. tb-driven MMP-1 but not MMP-7 gene expression and secretion. PAS acts by blocking PGE(2) production without affecting M. tb growth. In summary, p-aminosalicyclic acid decreases MMP-1 activity by inhibiting a p38 MAPK-PG signaling cascade, suggesting that this pathway is a therapeutic target to reduce inflammatory tissue destruction in tuberculosis.
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Peroxisome proliferator-activated receptor gamma (PPARgamma) is constitutively expressed at high levels in healthy alveolar macrophages, in contrast to other tissue macrophages and blood monocytes. PPARgamma ligands have been shown to down-regulate IFN-gamma-stimulated inducible NO synthase (iNOS) in macrophages. Because NO is an important inflammatory mediator in the lung, we hypothesized that deletion of alveolar macrophage PPARgamma in vivo would result in up-regulation of iNOS and other inflammatory mediators. ⋯ To test whether these alterations were due to the lack of PPARgamma, PPARgamma KO mice were intratracheally inoculated with a PPARgamma lentivirus construct. PPARgamma transduction resulted in significantly decreased iNOS and IFN-gamma mRNA expression, as well as reduced BAL lymphocytes. These results suggest that lack of PPARgamma in alveolar macrophages disrupts lung homeostasis and results in a Th1-like inflammatory response.
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IL-20, an IL-10 family member, is involved in various inflammatory diseases, such as psoriasis, rheumatoid arthritis, and atherosclerosis. We investigated whether hypoxia in vitro and an in vivo model of ischemic stroke would up-regulate IL-20 expression. In vitro, IL-20 expression increased in hypoxic HaCaT, HEK293 cells, chondrocytes, monocytes, and glioblastoma cells. ⋯ IL-20 induced cell proliferation in GBM8901 cells by activating the JAK2/STAT3 and ERK1/2 pathways. IL-20 also induced production of IL-1beta, IL-8, and MCP-1 in GBM8901 cells. We conclude that IL-20 was responsive to hypoxia in vitro and in the ischemic stroke model and that up-regulation of IL-20 in the ischemic brain may contribute to brain injury.