krn-7000 and Peritonitis

Invariant NKT (iNKT) cells are a conserved αβTCR(+) T cell population that can swiftly produce large amounts of cytokines, thereby activating other leukocytes, including neutrophilic granulocytes (neutrophils). In this study, we investigated the reverse relationship, showing that high neutrophil concentrations suppress the iNKT cell response in mice and humans. Peripheral Vα14 iNKT cells from spontaneously neutrophilic mice produced reduced cytokines in response to the model iNKT cell Ag α-galactosyl ceramide and expressed lower amounts of the T-box transcription factor 21 and GATA3 transcription factor than did wild-type controls. This influence was extrinsic, as iNKT cell transcription factor expression in mixed chimeric mice depended on neutrophil count, not iNKT cell genotype. Transcription factor expression was also decreased in primary iNKT cells from the neutrophil-rich bone marrow compared with spleen in wild-type mice. In vitro, the function of both mouse and human iNKT cells was inhibited by coincubation with neutrophils. This required cell-cell contact with live neutrophils. Neutrophilic inflammation in experimental peritonitis in mice decreased iNKT cell T-box transcription factor 21 and GATA3 expression and α-galactosyl ceramide-induced cytokine production in vivo. This was reverted by blockade of neutrophil mobilization. Similarly, iNKT cells from the human peritoneal cavity expressed lower transcription factor levels during neutrophilic peritonitis. Our data reveal a novel regulatory axis whereby neutrophils reduce iNKT cell responses, which may be important in shaping the extent of inflammation.

Topics: Adult; Aged; Animals; Cell Communication; Cytokines; Female; Galactosylceramides; Gene Expression Regulation; Humans; Immunity, Cellular; Immunosuppression Therapy; Leukocyte Count; Male; Mice; Mice, Inbred C57BL; Middle Aged; Natural Killer T-Cells; Neutrophils; Peritonitis; Radiation Chimera; Species Specificity; Specific Pathogen-Free Organisms; Transcription Factors; Young Adult

In this study, we demonstrated that lipopolysaccharide (LPS) markedly increased nitric oxide (NO) production and indoleamine 2,3-dioxygenase (IDO) activity in mouse peritoneal cells in the presence of activated Valpha14 natural killer T cells. Moreover, LPS-induced NO production in peritoneal cells from IDO-knockout (KO) mice was more increased than that from wild-type mice. However, there was no significant difference in the expression of inducible nitric oxide synthase (iNOS) mRNA and protein between the wild-type and IDO-KO mice. No significant difference was also observed in the ratio of CD3- and DX5-positive cells and F4/80- and TLR4-positive cells in peritoneal cells between the wild-type and IDO-KO mice. Since the IDO activity was enhanced by an NO inhibitor, NO may be post-translationally consumed by inhibiting the IDO activity. IDO is well known to play an important role in immunosuppression during inflammatory disease. Therefore, the inhibition of IDO by NO may exacerbate inflammation in the peritoneal cavity.

Topics: Animals; Galactosylceramides; Immune Tolerance; Indoleamine-Pyrrole 2,3,-Dioxygenase; Interferon-gamma; Lipopolysaccharides; Lymphocyte Activation; Mice; Mice, Inbred C57BL; Mice, Knockout; Natural Killer T-Cells; Nitric Oxide; Nitric Oxide Synthase Type II; Peritoneum; Peritonitis; Receptors, Antigen, T-Cell, alpha-beta