A combination of hypoxia and lipopolysaccharide activates tristetraprolin to destabilize proinflammatory mRNAs such as tumor necrosis factor-alpha.

The American Journal of Pathology
Christian WernoBernhard Brüne

Abstract

Inflammation is often accompanied by hypoxia because of the high oxygen consumption of invading bacteria and immune cells. During resolution of inflammation, the formation of inflammatory mediators such as tumor necrosis factor-alpha (TNF-alpha), which is produced by macrophages, needs to be terminated. We show in RAW264.7 macrophages that TNF-alpha mRNA as well as intracellular and secreted TNF-alpha protein levels are reduced after prolonged incubations with lipopolysaccharide (LPS) under hypoxic conditions. The decrease in TNF-alpha was mediated by destabilization of TNF-alpha mRNA via a 3'-untranslated region-dependent mechanism. Specifically, the RNA-binding protein tristetraprolin (TTP) increased at mRNA and protein levels after 16-hour incubations with LPS under hypoxia. Interestingly, TTP accumulated in a dephosphorylated and active form, and this accumulation was attributable to reduced p38 mitogen-activated protein kinase activity under these conditions. Knockdown of TTP by small interfering RNA abolished destabilization of TNF-alpha mRNA. Prolonged incubations with LPS under hypoxia also reduced mRNA amounts and stability of other proinflammatory mediators such as macrophage inflammatory protein-2, interleukin-6, and...Continue Reading

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Citations

Feb 22, 2012·Microbial Pathogenesis·Josefa B da SilvaElizabeth A L Martins
Apr 15, 2017·The American Journal of Pathology·Kasra KhalajChandrakant Tayade
Oct 22, 2015·Scientific Reports·Lorena HärdleHeiko Mühl
Apr 28, 2012·European Journal of Immunology·Jessica HoppstädterAlexandra K Kiemer
Apr 12, 2012·The Journal of Immunology : Official Journal of the American Association of Immunologists·Lian-Qun QiuPerry J Blackshear
Dec 3, 2016·Biochemical Society Transactions·Andrew R Clark, Jonathan L E Dean

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