IL-10-induced TNF-alpha mRNA destabilization is mediated via IL-10 suppression of p38 MAP kinase activation and inhibition of HuR expression

Johnson Rajasingh, Evelyn Bord, Corinne Luedemann, Jun Asai, Hiromichi Hamada, Tina Thorne, Gangjian Qin, David Goukassian, Yan Zhu, Douglas W. Losordo, Raj Kishore

Research output: Contribution to journalArticlepeer-review

116 Scopus citations

Abstract

Inflammation plays an essential role in vascular injury and repair. Mononuclear phagocytes are important contributors in these processes, in part, via adhesive interactions and secretion of proinflammatory cytokines. The antiinflammatory cytokine interleukin (IL)-10 suppresses such responses via deactivation of monocytes/macrophages and repression of inflammatory cytokine expression. The mechanisms of IL-10's suppressive action are, however, incompletely characterized. Here, we report that systemic IL-10 treatment after carotid artery denudation in mice blunts inflammatory cell infiltration and arterial tumor necrosis factor (TNF) expression. At the molecular level, in a human monocytic cell line, U937 IL-10 suppressed LPS-induced mRNA expression of a number of inflammatory cytokines, mainly via posttranscriptional mRNA destabilization. Detailed studies on IL-10 regulation of TNF-α mRNA expression identified AU-rich elements (ARE) in the 3′ untranslated region as a necessary determinant of IL-10-mediated TNF-α mRNA destabilization. IL-10 sensitivity to TNF depends on the ability of IL-10 to inhibit the expression and mRNA-stabilizing protein HuR and via IL-10 mediated repression of p38 mitogen-activated protein (MAP) kinase activation. Because IL-10 function and signaling are important components for control of inflammatory responses, these results may provide insights necessary to develop strategies for modulating vascular repair and other accelerated arteriopathies, including transplant vasculopathy and vein graft hyperplasia.

Original languageEnglish
Pages (from-to)E1393-E1403
JournalFASEB Journal
Volume20
Issue number12
DOIs
StatePublished - Oct 2006
Externally publishedYes

Keywords

  • AU-rich elements
  • mRNA stability

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