REGULATORY EFFECTS OF ENDOGENOUS INTERLEUKIN-1 RECEPTOR ANTAGONIST PROTEIN IN IMMUNOGLOBULIN-G IMMUNE COMPLEX-INDUCED LUNG INJURY

IL-1 receptor antagonist (IL-1Ra) has regulatory effects on IL-1 activ ity both in vitro and in vivo. In the IgG immune complex model of lung injury in rats, exogenously administered human IL-1Ra suppressed neut rophil recruitment and ensuing lung injury. In this study, we sought t o determine if endogenous rat IL-1Ra might regulate this lung-inflamma tory response. By Northern blot analysis of lung mRNA and Western anal ysis of bronchoalveolar lavage (BAL) fluids, rat IL-1Ra expression was found to increase during development of inflammation in IgG immune co mplex-mediated alveolitis. By immunostaining, alveolar macrophages and recruited neutrophils were the apparent sources of IL-1Ra. In vivo bl ocking of endogenous IL-1Ra resulted in a 53% increase in lung vascula r permeability and a 180% increase in BAL fluid neutrophils. In compan ion studies, a significant increase in BAL IL-1 beta was found, wherea s no significant change in TNF-alpha activity was observed. Whereas th e in vivo regulatory effects of IL-1Ra appear to be limited to IL-1 be ta, IL-10 regulates both IL-1 beta and TNF-alpha in this model, reflec ted by a 48% increase in BAL IL-1 beta in rats treated with anti-IL-10 . These findings suggest that IL-1Ra is an intrinsic regulator of infl ammatory injury after deposition of IgG immune complexes and that it r egulates production of IL-1 beta.