INDUCTION OF HAEM OXYGENASE CONTRIBUTES TO THE SYNTHESIS OF PRO-INFLAMMATORY CYTOKINES IN RE-OXYGENATED RAT MACROPHAGES: ROLE OF cGMP

Author： Tamion F. Richard V. Lyoumi S. Hiron M. Bonmarchand G. Leroy J. Daveau M. Thuillez C. Lebreton J-P.

Publisher： Academic Press

ISSN： 1043-4666

Source： Cytokine, Vol.11, Iss.5, 1999-05, pp. : 326-333

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Abstract

Macrophage activation and the resulting inflammatory response may be a major component of tissue injury upon hypoxia and re-oxygenation. Activation of the haem oxygenase (HO)/carbon monoxide (CO) pathway may be an important regulator of the inflammatory response, through production of cyclic 3′, 5′-monophosphate (cGMP). We have assessed whether HO contributes to the increased production of the pro-inflammatory cytokines TNF-α and IL-6 in re-oxygenated 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 (SnPP-9) given during re-oxygenation. Hypoxia and re-oxygenation also increased IL-6 and TNF-α mRNA expression, as well as IL-6 and TNF-α concentrations in the cell supernatant. These increases were nullified by SnPP-9 and by Methylene Blue, an inhibitor of guanylate cyclase, but were not affected by L-NNA, an inhibitor of NO synthesis. The inhibitory effect of SnPP on the synthesis of cytokines was reversed by co-administration of the stable analogue of cGMP, 8-Br-cGMP.Our results indicate that activation of haem oxygenase and of the CO/cGMP pathway is a major stimulus for the synthesis and release of pro-inflammatory cytokines in re-oxygenated macrophages. This pathway may play a central role in pathological situations in which local tissue hypoxia/re-oxygenation triggers a systemic inflammatory response, for example in patients with shock.