INTERLEUKIN-10 IS A CENTRAL REGULATOR OF THE RESPONSE TO LPS IN MURINE MODELS OF ENDOTOXIC-SHOCK AND THE SHWARTZMAN REACTION BUT NOT ENDOTOXIN TOLERANCE

Previous studies in vivo have shown that IL-10 infusion can prevent le thal endotoxic shock. Mice deficient in the production of IL-10 (IL1OT ) were used to investigate the regulatory role of IL-10 in the respons es to LPS in three experimental systems. In a model of acute endotoxic shock, it was found that the lethal dose of LPS for IL1OT mice was 20 -fold lower than that for wild type (wt) mice suggesting that endogeno us IL-10 determines the amount of LPS which can be tolerated without d eath. The high mortality rate of IL1OT mice challenged with modest dos es of LPS was correlated to the uncontrolled production of TNF as trea tment with anti-TNF antibody (Ab) resulted in 70% survival. Additional studies suggested that IL-10 mediates protection by controlling the e arly effecters of endotoxic shock (e.g., TNF alpha) and that it is inc apable of directly antagonizing the production and/or actions of late appearing effector molecules (e.g., nitric oxide). We also found that IL10T mice were extremely vulnerable to a generalized Shwartzman react ion where prior exposure to a small amount of LPS primes the host for a lethal response to a subsequent sublethal dose. The priming LPS dose for IL1OT mice was 100-fold lower than that required to prime wt mice implying that IL-10 is important for suppressing sensitization. In ag reement with this assumption, IL-10 infusion was found to block the se nsitization step. Interestingly, IL-10 was not the main effector of en dotoxin tolerance as IL1OT mice could be tolerized to LPS. Furthermore , IL-10 infusion could not substitute for the desensitizing dose of LP S. These results show that IL-10 is a critical component of the host's natural defense against the development of pathologic responses to LP S although it is not responsible for LPS-induced tolerance.