TNF RECEPTOR-DEFICIENT MICE REVEAL DIVERGENT ROLES FOR P55 AND P75 INSEVERAL MODELS OF INFLAMMATION

The pleiotropic activities of the potent proinflammatory cytokine TNF are mediated by two structurally related, but functionally distinct, r eceptors, p55 and p75, that are coexpressed on most cell types. The ma jority of biologic responses classically attributed to TNF are mediate d by p55. In contrast, p75 has been proposed to function as both a TNF antagonist by neutralizing TNF and as a TNF agonist by facilitating t he interaction between TNF and p55 at the cell surface. We have examin ed the roles of p55 and p75 in mediating and modulating the activity o f TNF in vivo by generating and examining mice genetically deficient i n these receptors. Selective deficits in several host defense and infl ammatory responses are observed in mice lacking p55 or both p55 and p7 5, but not in mice lacking p75. In these models, the activity of p55 i s not impaired by the absence of p75, arguing against a physiologic ro le for p75 as an essential element of p55-mediated signaling. In contr ast, exacerbated pulmonary inflammation and dramatically increased end otoxin induced serum TNF levels in mice lacking p75 suggest a dominant role for p75 in suppressing TNF-mediated inflammatory responses. In s ummary, these data help clarify the biologic roles of p55 and p75 in m ediating and modulating the biologic activity of TNF and provide genet ic evidence for an antagonistic role of p75 in vivo.