IL-10-induced TNF-alpha mRNA destabilization is mediated via IL-10 suppression of p38 MAP kinase activation and inhibition of HuR expression.
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-alpha mRNA expression identified AU-rich elements (ARE) in the 3' untranslated region as a necessary determinant of IL-10-mediated TNF-alpha 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.
Rajasingh
Johnson
J
Division of Cardiovascular Research, Caritas St. Elizabeth's Medical Center, Tufts University School of Medicine, Boston, Massachusetts 02135, USA.
Bord
Evelyn
E
Luedemann
Corinne
C
Asai
Jun
J
Hamada
Hiromichi
H
Thorne
Tina
T
Qin
Gangjian
G
Goukassian
David
D
Zhu
Yan
Y
Losordo
Douglas W
DW
Kishore
Raj
R
D000818:Animals; D000954:Antigens, Surface / Q000235:genetics; D020212:Carotid Artery Injuries; D002460:Cell Line; D016207:Cytokines / Q000032:analysis; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D051959:ELAV Proteins; D000067780:ELAV-Like Protein 1; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D016753:Interleukin-10 / Q000494:pharmacology* / Q000627:therapeutic use; D051379:Mice; D009000:Monocytes; D012323:RNA Processing, Post-Transcriptional; D020871:RNA Stability / Q000187:drug effects; D012333:RNA, Messenger / Q000187:drug effects; D016601:RNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*
D000954:Antigens, Surface; D016207:Cytokines; D051959:ELAV Proteins; D000067780:ELAV-Like Protein 1; C098770:ELAVL1 protein, human; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D048051:p38 Mitogen-Activated Protein Kinases