Heme oxygenase-1 inhibits TNF-alpha-induced apoptosis in cultured fibroblasts

Heme oxygenase (HO)-1 catalyzes the oxidative cleavage of heme to yield equ imolar amounts of biliverdin, iron, and carbon monoxide. HO-1 is a stress r esponse protein, the induction of which is associated with protection again st oxidative stress. The mechanism(s) of protection is not completely eluci dated, although it is suggested that one or more of the catalytic by-produc ts provide antioxidant functions either directly or indirectly. The involve ment of reactive oxygen species in apoptosis raised the question of a possi ble role for HO-1 in programmed cell death. Using the tetracycline-regulate d expression system, we show here that conditional overexpression of HO-1 p revents tumor necrosis factor-alpha-induced apoptosis in murine L929 fibrob lasts. Inhibition of apoptosis was not observed in the presence of tin prot oporphyrin, a specific inhibitor of HO activity, and in cells overexpressin g antisense HO-1. Interestingly, exogenous administration of a low concentr ation of carbon monoxide also prevented tumor necrosis factor-alpha-induced apoptosis in L929 fibroblasts. Inhibition of tumor necrosis factor-alpha-i nduced apoptosis by HO-1 overexpression was reversed by 1H-(1,2,4)oxadiazol o(4,3-a)quinoxalin-1-one, an inhibitor of guanylate cyclase, which is a tar get enzyme for carbon monoxide. Taken together, our data suggest that the a ntiapoptotic effect of HO-1 may be mediated via carbon monoxide.