Induction of haem oxygenase contributes to the synthesis of pro-inflammatory cytokines in re-oxygenated rat macrophages: Role of cGMP

Macrophage activation and the resulting inflammatory response may be a majo r component of tissue injury upon hypoxia and re-oxygenation. Activation of the haem oxygenase (HO)/carbon monoxide (CO) pathway may be an important r egulator of the inflammatory response, through production of cyclic 3', 5'- monophosphate (cGMP), We have assessed whether HO contributes to the increa sed production of the pro-inflammatory cytokines TNF-alpha and IL-6 in re-o xygenated rat peritoneal macrophages, Hypoxia/re-oxygenation markedly increased levels of HO-1 mRNA and cGMP, The increase in cGMP was reduced by the HO-1 inhibitor tin-protoporphyrin (SnP P-9) given during re-oxygenation, Hypoxia and re-oxygenation also increased IL-6 and TNF-alpha mRNA expression, as well as IL-6 and TNF-alpha. concent rations in the cell supernatant, These increases were nullified by SnPP-9 a nd by Methylene Blue, an inhibitor of guanylate cyclase, but were not affec ted by L-NNA, an inhibitor of NO synthesis. The inhibitory effect of SnPP o n the synthesis of cytokines was reversed by co-administration of the stabl e analogue of cGMP, 8-Br-cGMP, Our results indicate that activation of haem oxygenase and of the CO/cGMP p athway is a major stimulus for the synthesis and release of pro-inflammator y cytokines in re-oxygenated macrophages, This pathway may play a central r ole in pathological situations in which local tissue hypoxia/re-oxygenation triggers a systemic inflammatory response, for example in patients with sh ock. (C) 1999 Academic Press.