Anti-inflammatory properties of the PI3K pathway are mediated by IL-10/DUSP regulation.
Resolution of inflammation is an important hallmark in the course of infectious diseases. Dysregulated inflammatory responses may have detrimental consequences for the affected organism. Therefore, tight regulation of inflammation is indispensable. Among numerous modulatory signaling pathways, the PI3K/PTEN signaling pathway has been proposed recently to be involved in the regulation of innate immune reactions. Here, we attempted to elucidate molecular mechanisms that contribute to the modulatory properties of the PI3K signaling pathway in inflammation. PTEN-deficient macrophages, which harbor constitutively active PI3Ks, were analyzed in response to gram-negative bacteria and PAMPs such as LPS. PTEN-deficient cells showed reduced inflammatory cytokine production, which was accompanied by reduced MAPK signaling activation in early- as well as late-phase activation. Simultaneously, we found increased levels of the MKP DUSP1, as well as the anti-inflammatory cytokine IL-10. Our data suggest that differential DUSP1 regulation coupled with enhanced IL-10 production contributes to the anti-inflammatory properties of the PI3K pathway.
Günzl
Philipp
P
Department of Vascular Biology and Thrombosis Research, Center for Biomolecular Medicine and Pharmacology, Medical University of Vienna, Vienna, Austria.
Bauer
Kathrin
K
Hainzl
Eva
E
Matt
Ulrich
U
Dillinger
Barbara
B
Mahr
Benedikt
B
Knapp
Sylvia
S
Binder
Bernd R
BR
Schabbauer
Gernot
G
D040981:Acinetobacter baumannii / Q000276:immunology; D000818:Animals; D054638:Dual Specificity Phosphatase 1 / Q000235:genetics / Q000502:physiology*; D007249:Inflammation / Q000517:prevention & control*; D016753:Interleukin-10 / Q000502:physiology*; D020935:MAP Kinase Signaling System; D008264:Macrophages / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000502:physiology; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D012333:RNA, Messenger / Q000032:analysis; D015398:Signal Transduction / Q000502:physiology*; D051193:Toll-Like Receptors / Q000502:physiology
D054638:Dual Specificity Phosphatase 1; D016753:Interleukin-10; D016328:NF-kappa B; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D012333:RNA, Messenger; D051193:Toll-Like Receptors; C517020:Dusp1 protein, mouse; C487757:Pten protein, mouse