Contribution of Toll-like receptor/myeloid differentiation factor 88 signaling to murine liver regeneration.
Toll-like receptors (TLRs) act as innate immune signal sensors and play central roles in host defense. Myeloid differentiation factor (MyD) 88 is a common adaptor molecule required for signaling mediated by TLRs. When the receptors are activated, cells bearing TLRs produce various proinflammatory cytokines in a MyD88-dependent manner. Liver regeneration following partial hepatectomy (PH) requires innate immune responses, particularly interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-alpha) production by Kupffer cells, although the recognition and activation processes are still unknown. We investigated whether TLR/MyD88 signaling is critical for induction of innate immune responses after PH. In Myd88(-/-) mice after PH, induction of expression of immediate early genes involved in hepatocyte replication and phosphorylation of STAT3 in the liver, and production of TNF-alpha/IL-6 by and activation of NF-kappaB in the Kupffer cells were grossly subnormal and were associated with impaired liver regeneration. However, TLR2, 4 and 9, which recognize gram-negative and -positive bacterial products, are not essential for NF-kappaB activation and IL-6 production after PH, which excludes a possible contribution of TLR2/TLR4 or TLR9 to MyD88-mediated pathways. In conclusion, the TLR/MyD88 pathway is essential for incidental liver restoration, particularly its early phase.
Seki
Ekihiro
E
First Department of Surgery, Hyogo College of Medicine, Nishinomiya, Japan.
Tsutsui
Hiroko
H
Iimuro
Yuji
Y
Naka
Tetsuji
T
Son
Gakuhei
G
Akira
Shizuo
S
Kishimoto
Tadamitsu
T
Nakanishi
Kenji
K
Fujimoto
Jiro
J
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D000943:Antigens, Differentiation / Q000502:physiology*; D005786:Gene Expression Regulation; D017781:Genes, Immediate-Early; D015850:Interleukin-6 / Q000096:biosynthesis; D008115:Liver Regeneration; D008297:Male; D008562:Membrane Glycoproteins / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000502:physiology*; D011971:Receptors, Immunologic / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D048868:Adaptor Proteins, Signal Transducing; D000943:Antigens, Differentiation; D015850:Interleukin-6; D008562:Membrane Glycoproteins; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B; D011956:Receptors, Cell Surface; D011971:Receptors, Immunologic; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha