The Journal of immunology : official journal of the American Association of Immunologists
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Hydrogen sulfide (H(2)S) up-regulates inflammatory response in several inflammatory diseases. However, to date, little is known about the molecular mechanism by which H(2)S provokes the inflammatory response in sepsis. Thus, the aim of this study was to investigate the signaling pathway underlying the proinflammatory role of H(2)S in cecal ligation and puncture (CLP)-induced sepsis. ⋯ As a result, pretreatment with PAG significantly reduced the production of cytokines and chemokines in sepsis, whereas exogenous H(2)S greatly increased it. In addition, pretreatment with PD98059, an inhibitor of ERK kinase (MEK-1), significantly prevented NaHS from aggravating systemic inflammation in sepsis. In conclusion, the present study shows for the first time that H(2)S may regulate systemic inflammatory response in sepsis via ERK pathway.
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In this study, we have addressed the role of H(2)S in modulating neutrophil migration in either innate (LPS-challenged naive mice) or adaptive (methylated BSA (mBSA)-challenged immunized mice) immune responses. Treatment of mice with H(2)S synthesis inhibitors, dl-propargylglycine (PAG) or beta-cyanoalanine, reduced neutrophil migration induced by LPS or methylated BSA (mBSA) into the peritoneal cavity and by mBSA into the femur/tibial joint of immunized mice. This effect was associated with decreased leukocyte rolling, adhesion, and P-selectin and ICAM-1 expression on endothelium. ⋯ The effects of NaHS on neutrophil migration both in vivo and in vitro, together with CXCR2 internalization and G protein-coupled receptor kinase 2 expression were prevented by the ATP-sensitive potassium (K(ATP)(+)) channel blocker, glybenclamide. Conversely, diazoxide, a K(ATP)(+) channel opener, increased neutrophil migration in vivo. Together, our data suggest that during the inflammatory response, H(2)S augments neutrophil adhesion and locomotion, by a mechanism dependent on K(ATP)(+) channels.
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OX40 is a member of the TNFR superfamily and has potent T cell costimulatory activities. OX40 also inhibits the induction of Foxp3(+) regulatory T cells (Tregs) from T effector cells, but the precise mechanism of such inhibition remains unknown. In the present study, we found that CD4(+) T effector cells from OX40 ligand-transgenic (OX40Ltg) mice are highly resistant to TGF-beta mediated induction of Foxp3(+) Tregs, whereas wild-type B6 and OX40 knockout CD4(+) T effector cells can be readily converted to Foxp3(+) T cells. ⋯ Importantly, memory CD4(+) T cells have a broad impact on the induction of Foxp3(+) Tregs regardless of their origins and Ag specificities. Our data suggest that one of the mechanisms by which OX40 inhibits the induction of Foxp3(+) Tregs is by inducing memory T cells in vivo. This finding may have important clinical implications in tolerance induction to transplanted tissues.