DEFECTIVE INFLAMMATORY RESPONSE IN INTERLEUKIN 6-DEFICIENT MICE

Systemic and localized inflammation elicit a number of host responses which include fever, cachexia, hypoglycemia, and major changes in the concentration of liver plasma proteins. Interleukin 6 (IL-6) is consid ered an important mediator of the inflammatory response, together with IL-1 and tumor necrosis factor alpha (TNF-alpha). The purpose of this study was to unequivocally determine the role of IL-6 in these phenom ena making use of IL-6-deficient mice that we have recently generated by gene targeting. We report here that in the absence of IL-6, mice ar e unable to mount a normal inflammatory response to localized tissue d amage generated by turpentine injection. The induction of acute phase proteins is dramatically reduced, mice do not lose body weight and onl y suffer from mild anorexia and hypoglycemia. In contrast, when system ic inflammation is elicited through the injection of bacterial lipopol ysaccharide (LPS), these parameters are altered to the same extent bot h in wild-type and IL-6-deficient mice, demonstrating that under these conditions IL-6 function is dispensable. Moreover, we show that LPS-t reated IL-6-deficient mice produce three times more TNP-alpha than wil d-type controls, suggesting that increased TNF-alpha production might be one of the compensatory mechanisms through which a normal response to LPS is achieved in the absence of IL-6. We also show that corticost erone is normally induced in IL-6-deficient mice, demonstrating that I L-6 is not required for the activation of the hypothalamic-pituitary-a drenal axis. Our results reinforce the idea that different patterns of cytokines are involved in systemic and localized tissue damage, and i dentify IL-6 as an essential mediator of the inflammatory response to localized inflammation.