We used gene targeting in embryonic stem cells to introduce an IL-lf3 null allele in mice. The IL-lft-deficient mice develop normally and are apparently healthy and fertile. The IL-18 null mice responded normally in models of contact and delayed-type hypersensitivity or followlng bacterial endotoxin LPS-induced inflammation. The IL-1% deficient mice showed equivalent resistance to Listeria monocytogenes compared with wild-type controls. In contrast, when challenged wlth turpentine, which causes localized Inflammation and tissue injury, the IL-lfl mutant mice exhibited an impaired acute-phase inflammatory response and were completely resistant to fever development and anorexia. These results highlight a central role for IL-lf3 as a pyrogen and a mediator of the acute-phase response in a subset of inflammatory disease models, and support the notion that blocklng the action of a single key cytokine can alter the course of specific immune and inflammatory responses. introduction

Mammalian interleukin-1 (IL-l) is a proinflammatory cytokine that is produced particularly by mononuclear phagocytes, but also by numerous other cell types, in response to injury and infection (reviewed by di Giovine and Duff, 1990; Dinarello, 1992; and references therein). The biological activity of IL-l is encoded bytwodistinct genes, termed