Defective inflammatory response in interleukin 6-deficient mice.

Abstract

SummarySystemic and localized inflammation elicit a number of host responses which include fever, cachexia, hypoglycemia, and major changes in the concentration of liver plasma proteins. Interlenkin 6 (IL-6) is considered an important mediator of the inflammatory response, together with IL-1 and tumor necrosis factor c~ (TNF-c 0. The purpose of this study was to unequivocally determine the role of IL-6 in these phenomena 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 are unable to mount a normal inflammatory response to localized tissue damage generated by turpentine injection. The induction of acute phase proteins is dramatically reduced, mice do not lose body weight and only suffer from mild anorexia and hypoglycemia. In contrast, when systemic inflammation is elicited through the injection of bacterial lipopolysaccharide (LPS), these parameters are altered to the same extent both in wild-type and IL-6-deficient mice, demonstrating that under these conditions IL-6 function is dispensable. Moreover, we show that LPS-treated IL-6-deficient mice produce three times more TNF-c~ than wild-type controls, suggesting that increased TNF-c~ 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 corticosterone is normally induced in IL-6-deficient mice, demonstrating that IL-6 is not required for the activation of the hypothahmicpituitary-adrenal axis. Our results reinforce the idea that different patterns of cytokines are involved in systemic and localized tissue damage, and identify IL-6 as an essential mediator of the inflammatory response to localized inflammation.

Effects of i.c.v. administration of interleukin-1 on sleep and body temperature of interleukin-6-deficient mice

“…There are numerous mechanisms by which IL-1 can increase NREM sleep, including direct actions on sleep-active neurons of the preoptic area of the hypothalamus (Alam et al, 2004;Baker et al, 2005) and on arousal-promoting serotonergic neurons of the dorsal raphe (Brambilla et al, 2007). Endogenous IL-6 exerts negative feedback control on TNF, and IL-6 KO mice exhibit an approximately threefold higher increase in serum TNF after immune challenge with LPS than do control mice (Fattori et al, 1994;Kozak et al, 1998). TNF is also involved in the regulation of NREM sleep and increases NREM sleep of mice (Fang et al, 1997).…”

IL-6 promoter polymorphisms in rheumatoid arthritis

“…22 Contradictory effects of IL-6 have also been reported in knockout models of this cytokine when examining the response to different inflammatory stimuli. While an overall normal inflammatory response, paralleled with three-fold higher TNF␣ levels, 24 resulted in IL-6 −/− mice after a systemic stimulus (LPS), an impaired response in these mice was observed when a local stimulus (turpentine) was used. 24,25 This is consistent with in vitro and in vivo evidence supporting the concept that the IL-6 system plays a sensitive role in local inflammatory reactions by amplifying leukocyte recruitment 26 and with the capacity of IL-6 to protect against LPS toxicity.…”

“…While an overall normal inflammatory response, paralleled with three-fold higher TNF␣ levels, 24 resulted in IL-6 −/− mice after a systemic stimulus (LPS), an impaired response in these mice was observed when a local stimulus (turpentine) was used. 24,25 This is consistent with in vitro and in vivo evidence supporting the concept that the IL-6 system plays a sensitive role in local inflammatory reactions by amplifying leukocyte recruitment 26 and with the capacity of IL-6 to protect against LPS toxicity. 9,27 In summary, the data from the present study indicate that the IL-6 promoter polymorphisms studied do not play a major role as genetic susceptibility factors for RA.…”

Capturing the onset of the common cold and its effects on iron absorption

“…For this reason, IL-1 has been proposed as more important than does IL-6 in inflammation-induced hypoferremia (Lee et al, 2005). Furthermore, the appearance of the acute-phase cascade appears to differ depending on the cause of the inflammation (Fattori et al, 1994). Future studies will undoubtedly reveal the complex intersections and interactions between different acute-phase mediators regulating iron kinetics.…”