IL-6 induces an anti-inflammatory response in the absence of SOCS3 in macrophages.
Whereas interleukin-6 (IL-6) is a proinflammatory cytokine, IL-10 is an anti-inflammatory cytokine. Although signal transducer and activator of transcription 3 (STAT3) is essential for the function of both IL-6 and IL-10, it is unclear how these two cytokines have such opposing functions. Here we show that suppressor of cytokine signaling 3 (SOCS3) is a key regulator of the divergent action of these two cytokines. In macrophages lacking the Socs3 gene or carrying a mutation of the SOCS3-binding site in gp130, the lipopolysaccharide-induced production of tumor necrosis factor (TNF) and IL-12 is suppressed by both IL-10 and IL-6. SOCS3 specifically prevents activation of STAT3 by IL-6 but not IL-10. Taken together, these data indicate that SOCS3 selectively blocks signaling by IL-6, thereby preventing its ability to inhibit LPS signaling.
Yasukawa
Hideo
H
Institute of Molecular Medicine and Department of Medicine, University of California San Diego, 9500 Gilman Drive, La Jolla, California 92093-0641, USA.
Ohishi
Masanobu
M
Mori
Hiroyuki
H
Murakami
Masaaki
M
Chinen
Takatoshi
T
Aki
Daisuke
D
Hanada
Toshikatsu
T
Takeda
Kiyoshi
K
Akira
Shizuo
S
Hoshijima
Masahiko
M
Hirano
Toshio
T
Chien
Kenneth R
KR
Yoshimura
Akihiko
A
D000818:Animals; D004268:DNA-Binding Proteins / Q000276:immunology; D005260:Female; D015151:Immunoblotting; D016753:Interleukin-10 / Q000276:immunology; D015850:Interleukin-6 / Q000276:immunology*; D008070:Lipopolysaccharides / Q000276:immunology; D017737:Macrophages, Peritoneal / Q000276:immunology / Q000378:metabolism; D008297:Male; D008562:Membrane Glycoproteins / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011506:Proteins / Q000276:immunology*; D012097:Repressor Proteins; D050796:STAT3 Transcription Factor; D015398:Signal Transduction / Q000276:immunology; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D015534:Trans-Activators / Q000276:immunology; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D018909:src Homology Domains / Q000276:immunology; D000093242:Interleukin-6 Inhibitors
D004268:DNA-Binding Proteins; D016753:Interleukin-10; D015850:Interleukin-6; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D011506:Proteins; D012097:Repressor Proteins; D050796:STAT3 Transcription Factor; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D000093242:Interleukin-6 Inhibitors; C491411:Socs3 protein, mouse; C494087:Stat3 protein, mouse