Divergent Mechanisms Utilized by SOCS3 to Mediate Interleukin-10 Inhibition of Tumor Necrosis Factor [alpha] and Nitric Oxide Production by Macrophages
The cytokine interleukin-10 (IL-10) potently inhibits macrophage function through activation of the transcription factor STAT3. The expression of SOCS3 (suppressor of cytokine signaling-3) has been shown to be induced by IL-10 in a STAT3-dependent manner. However, the relevance of SOCS3 expression t...
Saved in:
Published in | The Journal of biological chemistry Vol. 281; no. 10; pp. 6316 - 6324 |
---|---|
Main Authors | , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
American Society for Biochemistry and Molecular Biology
2006
|
Online Access | Get full text |
Cover
Loading…
Summary: | The cytokine interleukin-10 (IL-10) potently inhibits macrophage function through activation of the transcription factor STAT3. The expression of SOCS3 (suppressor of cytokine signaling-3) has been shown to be induced by IL-10 in a STAT3-dependent manner. However, the relevance of SOCS3 expression to the anti-inflammatory effect of IL-10 on macrophages has been controversial. Through kinetic analysis of the requirement for SOCS3 in IL-10 inhibition of lipopolysaccharide (LPS)-stimulated tumor necrosis factor-[alpha] (TNF[alpha]) transcription and translation, SOCS3 was found to be necessary for TNF[alpha] expression during the early phase, but not the late phase of IL-10 action. SOCS3 was essential for IL-10 inhibition of LPS-stimulated production of iNOS (inducible nitric-oxide synthase) protein and nitric oxide (NO). To determine the domains of SOCS3 protein important in mediating these effects, SOCS3[superscript -/-] macrophages were reconstituted with SOCS3 mutated for the SH2, KIR, SOCS box domains, and tyrosines 204 (Tyr²⁰⁴) and 221 (Tyr²²¹). The SH2 domain, SOCS box, and both Tyr²⁰⁴ and Tyr²²¹ were required for IL-10 inhibition of TNF[alpha] mRNA and protein expression, but interestingly the KIR domain was necessary only for IL-10 inhibition of TNF[alpha] protein expression. In contrast, Tyr²⁰⁴ and Tyr²²¹ were the only structural features of SOCS3 that were necessary in mediating IL-10 inhibition of iNOS protein expression and NO production. These data define SOCS3 as an important mediator of IL-10 inhibition of macrophage activation and that SOCS3 interferes with distinct LPS-stimulated signal transduction events through differing mechanisms. |
---|---|
ISSN: | 0021-9258 1083-351X |