Beneficial dysregulation of the time course of inflammatory mediators in lipopolysaccharide-induced tumor necrosis factor alpha factor-deficient mice.
To begin to understand the surprising survival of macrophage-specific lipopolysaccharide-induced tumor necrosis factor alpha factor-deficient (macLITAF(-/-)) animals after a lethal dose of lipopolysaccharide (LPS), as reported earlier, the present follow-up study focuses on the role of LITAF in the regulation of inflammatory cytokines secreted in response to lethal or sublethal doses of LPS administered to wild-type (WT) and macLITAF(-/-) mice. A time course study of kinase expression in peritoneal macrophages revealed increased phosphorylation of prosurvival kinases Akt, Erk1/2, and ribosomal S6 kinase (RSK) in macLITAF(-/-) mice compared to that in WT mice (n = 8), confirming their role in LPS-mediated diseases. macLITAF(-/-) mice (n = 8) survived a lethal dose of LPS plus d-galactosamine (d-GalN), expressing lower serum levels of pro- and anti-inflammatory cytokines than the WT levels. To extend our knowledge on LPS-induced inflammatory events, an effective sublethal dose of LPS was administered to the animals (n = 14). WT animals exhibited an acute inflammatory response that decreased after 4 h. Interestingly, macLITAF(-/-) mice exhibited an initial delay in the secretion of proinflammatory cytokines that peaked after 8 h and reached WT levels after 18 h. Anti-inflammatory cytokine secretions were initially delayed but increased after 4 h and remained elevated compared to WT levels, even after 18 h. Our results demonstrate that LITAF deficiency in vivo affects cytokines other than TNF-alpha and influences the balance between the pro- and anti-inflammatory cytokines, which protects the animals from the deleterious effects of an LPS-induced inflammatory response, resulting in a beneficial host regulation of inflammatory cytokines and in enhanced survival. Therapeutic intervention aimed at reducing LITAF via kinase modulators may prove useful in preventing LPS-induced mortality.
Srinivasan
Sreedevi
S
Department of Periodontology and Oral Biology, School of Dental Medicine, Boston University, Boston, MA 02118, USA.
Leeman
Susan E
SE
Amar
Salomon
S
D000818:Animals; D020869:Gene Expression Profiling; D018836:Inflammation Mediators / Q000097:blood / Q000276:immunology*; D008070:Lipopolysaccharides / Q000276:immunology* / Q000633:toxicity*; D017737:Macrophages, Peritoneal / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D011494:Protein Kinases / Q000096:biosynthesis; D016019:Survival Analysis; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000172:deficiency*
D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D011494:Protein Kinases