NEUTRALIZATION OF ENDOGENOUS IL-6 SUPPRESSES INDUCTION OF IL-1 RECEPTOR ANTAGONIST

IL-1 is a potent cytokine that promotes host defense and inflammation. These processes may be modulated by an IL-1 receptor antagonist (IL-1 Ra) that binds to and blocks IL-1 receptors. The objective of this stu dy was to define the cellular origin and regulation of IL-1Ra producti on during bacterial infection. Oral infection of mice with Yersinia en terocolitica resulted in expression of IL-1Ra mRNA and synthesis of IL -1Ra in Peyer's patches (PP), the local site of infection, as well as in noninfected organs such as spleens. By immunostaining, recruited ci rculating neutrophils were identified to be the primary source of IL-1 Ra in tissues. Only approximately 20% of the IL-1Ra-staining cells wer e accounted for by inflammatory macrophages. Strikingly, neutralizatio n of. IL-6 by anti-IL-6 antiserum caused a suppression of both IL-1Ra mRNA in PP and synthesis of IL-1Ra in circulating neutrophils. Confirm atory evidence that IL-6 participates in the generation of IL-1Ra was obtained when rlL-6 induced, and anti-IL-6 antiserum blocked, IL-1Ra e xpression in cultures of macrophage and polymorphonuclear leukocytes ( PMN). These findings suggest that IL-6 induced induction of IL-1Ra may provide a negative feedback loop, facilitating resolution of the infl ammatory response locally and presumably at remote sites of infection.