Interleukin-10 targets p38 MAPK to modulate ARE-dependent TNF mRNA translation and limit intestinal pathology.
Interleukin-10 (IL-10) is a key inhibitory signal of inflammatory responses that regulates the production of potentially pathogenic cytokines like tumor necrosis factor (TNF). We show here that the development of chronic intestinal inflammation in IL-10-deficient mice requires the function of TNF, indicating that the IL-10/TNF axis regulates mucosal immunity. We further show that IL-10 targets the 3' AU-rich elements (ARE) of TNF mRNA to inhibit its translation. Moreover, IL-10 does not alter TNF mRNA stability, and its action does not require the presence of the stability-regulating ARE binding factor tristetraprolin, indicating a differential assembly of stability and translation determinants on the TNF ARE. Inhibition of TNF translation by IL-10 is exerted mainly by inhibition of the activating p38/MAPK-activated protein kinase-2 pathway. These results demonstrate a physiologically significant cross-talk between the IL-10 receptor and the stress-activated protein kinase modules targeting TNF mRNA translation. This cross-talk is necessary for optimal TNF production and for the maintenance of immune homeostasis in the gut.
Kontoyiannis
D
D
Institute of Immunology, BSRC 'Alexander Fleming', 166 72 Vari, Greece.
Kotlyarov
A
A
Carballo
E
E
Alexopoulou
L
L
Blackshear
P J
PJ
Gaestel
M
M
Davis
R
R
Flavell
R
R
Kollias
G
G
D000818:Animals; D002469:Cell Separation; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D016753:Interleukin-10 / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D007422:Intestines / Q000473:pathology*; D047908:Intracellular Signaling Peptides and Proteins; D008070:Lipopolysaccharides / Q000494:pharmacology; D008262:Macrophage Activation; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D014176:Protein Biosynthesis / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics*; D013379:Substrate Specificity; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics*; D048051:p38 Mitogen-Activated Protein Kinases; D000099190:MAP-Kinase-Activated Kinase 2
D016753:Interleukin-10; D047908:Intracellular Signaling Peptides and Proteins; D008070:Lipopolysaccharides; D020928:Mitogen-Activated Protein Kinases; D017346:Protein Serine-Threonine Kinases; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D048051:p38 Mitogen-Activated Protein Kinases; D000099190:MAP-Kinase-Activated Kinase 2