Phosphatase PTP1B negatively regulates MyD88- and TRIF-dependent proinflammatory cytokine and type I interferon production in TLR-triggered macrophages.
Toll-like receptors (TLRs) are primary sensors to detect conserved patterns on microorganisms, thus acting as the important components of innate immunity against invading pathogens. Protein tyrosine phosphatase-1B (PTP1B) has been shown to be a critical negative regulator of insulin pathway and other cellular signaling, however, whether and how PTP1B regulates TLR-triggered innate response remain to be investigated. We report here that PTP1B can markedly decrease TNF-alpha, IL-6 and IFN-beta production by macrophages stimulated with LPS, CpG ODN, or Poly I:C. Accordingly, knockdown of endogenous PTP1B expression increases production of TNF-alpha, IL-6 and IFN-beta in macrophages stimulated with TLR ligands. Phosphatase activity-disrupted mutant PTP1B cannot inhibit TLR-triggered production of proinflammatory cytokines and IFN-beta, indicating PTP1B exerts its suppressive activity in phosphatase-dependent manner. PTP1B inhibits TLR ligands-induced activation of MAPKs, NF-kappaB, and IRF3, furthermore, co-transfection of PTP1B inhibits both MyD88- and TRIF-induced transcription of TNF-alpha and IFN-beta reporter genes in a dose-dependent manner. In addition, PTP1B inhibits LPS-induced Tyk2 and STAT1 activation. Therefore, we demonstrate that phosphatase PTP1B is a physiological negative regulator of TLR signaling via suppression of both MyD88- and TRIF-dependent production of proinflammatory cytokine and IFN-beta in macrophages. Our results provide new mechanistic explanation for negative regulation TLR response and suggest PTP1B as a potential target for the intervention of the inflammatory diseases.
Institute of Immunology and National Key Laboratory of Medical Immunology, Second Military Medical University, 800 Xiangyin Road, Shanghai 200433, China.
Hongmei
H
Xu
Huazhang
H
An
Jin
J
Hou
Chaofeng
C
Han
Pin
P
Wang
Yizhi
Y
Yu
Xuetao
X
Cao
D033942:Adaptor Proteins, Vesicular Transport / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D015536:Down-Regulation; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism*; D007370:Interferon Type I / Q000378:metabolism*; D008262:Macrophage Activation / Q000276:immunology; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism*; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1 / Q000502:physiology*; D015398:Signal Transduction / Q000276:immunology; D051193:Toll-Like Receptors / Q000276:immunology / Q000378:metabolism
D033942:Adaptor Proteins, Vesicular Transport; D016207:Cytokines; D018836:Inflammation Mediators; D007370:Interferon Type I; D053594:Myeloid Differentiation Factor 88; C470409:TICAM1 protein, human; D051193:Toll-Like Receptors; C516607:PTPN1 protein, human; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1