Tristetraprolin Mediates Anti-Inflammatory Effects of Carbon Monoxide on Lipopolysaccharide-Induced Acute Lung Injury

Abstract

Low-dose inhaled carbon monoxide is reported to suppress inflammatory responses and exhibit a therapeutic effect in models of lipopolysaccharide (LPS)-induced acute lung injury (ALI). However, the precise mechanism by which carbon monoxide confers protection against ALI is not clear. Tristetraprolin (UP; official name ZFP36) exerts anti-inflammatory effects by enhancing decay of proinflammatory cytokine mRNAs. With the use of TIP knockout mice, we demonstrate here that the protection by carbon monoxide against LPS-induced ALT is mediated by UP. Inhalation of carbon monoxide substantially increased the pulmonary expression of TTP. carbon monoxide markedly enhanced the decay of mRNA-encoding inflammatory cytokines, blocked the expression of inflammatory cytokines, and decreased tissue damage in LPS-treated lung tissue. Moreover, knockout of TIP abrogated the anti-inflammatory and tissue-protective effects of carbon monoxide in LPS-induced ALT. These results suggest that carbon monoxide-induced TTP mediates the protective effect of carbon monoxide against LPS-induced ALI by enhancing the decay of mRNA encoding proinflammatory cytokines.