Constitutive shedding of both p55 and p75 murine TNF receptors in vivo

Recently, we reported the generation and characterization of hamster mAbs specific for the murine p55 and p75 TNF receptors. Upon characterizing these mAbs in vivo, we discovered that administration of TNF receptor-specific mAb to normal mice resulted in the linear accumulation of the appropriate class of soluble TNF receptor in the circulation. The mechanism underlying soluble receptor accumulation was found to be due to an abrogation of the clearance of constitutively shed soluble receptor by receptor-specific mAb. Levels of p55 or p75 accumulated in the presence of nonblocking, nonagonistic TNF receptor mAb were capable of inhibiting murine TNF-induced responses in vivo. These results document that both p55 and p75 are constitutively shed in substantial amounts in vivo and suggest that the process of constitutive TNF receptor shedding plays an important role in regulating TNF activity under physiologic conditions.