STAT4 and STAT6 regulate systemic inflammation and protect against lethal endotoxemia

Members of the signal transducer and activator of transcription (STAT) fami ly are transcription factors that mediate many of the effects of pro- and a nti-inflammatory cytokines. The progressive systemic inflammatory response induced by endotoxin is mediated by overzealous cytokine production. Here w e identify STAT4 and STAT6 as critical regulators of the systemic inflammat ory response to endotoxin. Mice deficient for STAT4 or STAT6 were highly su sceptible to lethal endotoxemia. In STAT4(-/-) mice, antibody blockade of I L-12 prevented mortality, suggesting that STAT4 confers protection, while a nother signaling pathway mediates the detrimental effects of IL-12. In STAT 6(-/-) mice we observed dysregulated activation of the transcription factor NF-kappaB, resulting in augmented production of proinflammatory cytokines and chemokines. Furthermore, STAT6(-/-) mice displayed increased organ accu mulation of leukocytes and significant hepatocellular injury. These finding s demonstrate that STAT4 and STAT6 confer protection against endotoxin-indu ced death and that for STAT6 these protective effects occur through the reg ulation of NF-kappaB activation and subsequent production of proinflammator y cytokines and chemokines.