A question of balance: ups and downs of mucosal inflammation.

Editorial Cytokines such as IL-I, TNFa, GM-CSF, and members of the chemokine a and 3 family (e.g., IL-8, MCP-l), have marked proinflammatory effects. These proinflammatory effects can be countered, in part, by other cytokines that have potent anti-inflammatory activities (e.g., TGF-P3I, IL-10) or by the binding of proinflammatory cytokines to soluble cytokine receptors in the extracellular milieu. In the case of IL-i, an additional novel mechanism can downregulate its proinflammatory activity. This involves the production and secretion of a naturally occurring protein, termed IL-i receptor antagonist (IL-lra). IL-Ira is structurally related to IL-1 and binds to type I IL-1 receptors. Since IL-lra has no intrinsic signaling activity through the IL-1 receptor, it, in effect, blocks this receptor. Administration of sufficient quantities of IL-ira can decrease the inflammatory response in a number of model systems in which an important proinflammatory role of IL-1 has been documented (1). However , less is known regarding the importance of endogenously produced IL-Ira in downregulating the inflammatory response in vivo in acute inflammatory reactions in which IL-1 has a documented role. In this issue of the JCI, Ferretti et al. (2) add to our knowledge in this area through studies using a model of acute colitis. This model involves the induction of an acute colitis in rabbits by intrarectal administration of formaldehyde followed by intravenous injection of immune complexes in antigen excess. The ensuing cellular infiltrate includes neutrophils and eosinophils, and is accompanied by crypt abscesses, epithelial cell degenera-tion, edema, and mucosal necrosis. In two of their prior studies, IL-1 production and colonic tissue levels of IL-i in this model correlated with the degree of inflammation (3, 4). Moreover, administration of IL-Ira suppressed colonic inflammation and the colonic production of PGE2 and LTB4, mediators thought to be important in the pathogenesis of this inflammatory response. The report in this issue of the JCI addresses two important issues which further validate the role endogenous IL-1 and IL-Ira may play in the induction and regulation of acute intestinal inflammation. The experiments first demonstrate that, temporally , the production of IL-Ira in the colon increases 48 h after the induction of colitis, a time which is delayed with respect to endogenous IL-1 production, but precedes the significant decrease in endogenous IL-i production associated with the resolution of acute colitis. Second, in studies in which a neutralizing antibody against IL-Ira was administered in vivo, the investigators report a significant …