Interleukin-10 inhibits tumor necrosis factor-α production in lipopolysaccharide-stimulated RAW 264.7 cells through reduced MyD88 expression

Abstract

The mechanism of interleukin (IL)-10-mediated inhibition of tumor necrosis factor (TNF)-α production was studied by lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophage cells. IL-10 inhibited TNF-α production transiently at an early stage after LPS stimulation. IL-10 inhibited the activation of nuclear factor (NF)-κB, p38 and stress-activated protein kinase (SAPK) in LPS-stimulated RAW 264.7 cells. Although the level of MyD88 protein increased in response to LPS, IL-10 prevented the LPS-induced MyD88 augmentation. There was no significant difference in the MyD88 mRNA expression between the cells pretreated with or without IL-10 in response to LPS. Therefore, IL-10 was suggested to inhibit LPS-induced TNF-α production via reduced MyD88 expression.

Keywords

IL-10 LPS MyD88 TNF-α TLR4

References

Grutz G. New insights into the molecular mechanism of interleukin-10-mediated immunosuppression . J Leukoc Biol 2005; 77: 3-15.

Akira S. Toll-like receptor signaling. J Biol Chem 2003; 278: 38105-38108.

O'Neill LA How Toll-like receptors signal: what we know and what we don't know. Curr Opin Immunol 2006; 18: 3-9.

Yamamoto M. , Sato S. TRAM is specifically involved in the Toll-like receptor 4-mediated MyD88-independent signaling pathway. Nat Immunol 2003; 4: 1144-1150.

Kopp E. , Medzhitov R. Recognition of microbial infection by Toll-like receptors. Curr Opin Immunol 2003; 15: 396-401.

Wang P. , Wu P. , Siegel MI , Egan RW , Billah MM Interleukin (IL)-10 inhibits nuclear factor kappa B (NF kappa B) activation in human monocytes. IL-10 and IL-4 suppress cytokine synthesis by different mechanisms. J Biol Chem 1995; 270: 9558-9563.

Schottelius AJ , Mayo MW , Sartor RB , Baldwin Jr AS Interleukin-10 signaling blocks inhibitor of kappaB kinase activity and nuclear factor-kappaB DNA binding . J Biol Chem 1999 ; 274: 31868-31874.

Kontoyiannis D. , Kotlyarov A. , Carballo E. et al. Interleukin-10 targets p38 MAPK to modulate ARE-dependent TNF-alpha mRNA translation and limit intestinal pathology . EMBO J 2001; 20: 3760-3770.

Qasimi P. , Ming-Lum A. , Ghanipour A. et al. Divergent mechanisms utilized by SOCS3 to mediate interleukin-10 inhibition of tumor necrosis factor-alpha and nitric oxide production by macrophages . J Biol Chem 2006; 281: 6316-6324.

10.

Wessells J. , Baer M. , Young HA et al. BCL-3 and NF-kappaB p50 attenuate lipopolysaccharide-induced inflammatory responses in macrophages. J Biol Chem 2004; 279: 49995-50003.

11.

Zou W. , Amcheslavsky A. , Takeshita S. , Drissi H. , Bar-Shavit Z. TNF-alpha expression is transcriptionally regulated by RANK ligand . J Cell Physiol 2005; 202: 371-378.

12.

Kawai T. , Akira S. TLR signaling. Cell Death Differ 2006 ; 13: 816-825.

13.

Campbell J. , Ciesielski CJ , Hunt AE et al. Novel mechanism for TNF-alpha regulation by p38 MAPK: involvement of NF-kappaB with implications for therapy in rheumatoid arthritis. J Immunol 2004; 173: 6928-6937.

14.

Yao J. , Mackman N. , Edgington TS , Fan ST Lipopolysaccharide induction of the tumor necrosis factor-alpha promoter in human monocytic cells. Regulation by Egr-1, c-Jun, and NF-kappaB transcription factors. J Biol Chem 1997; 272: 17795-17801.

15.

Driessler F. , Venstrom K. , Sabat R. , Asadullah K. , Schottelius AJ Molecular mechanisms of interleukin-10-mediated inhibition of NF-kappaB activity: a role for p50. Clin Exp Immunol 2004; 135: 64-73.

16.

Shames BD , Selzman CH , Meldrum DR et al. Interleukin-10 stabilizes inhibitory kappaB-alpha in human monocytes . Shock 1998; 10: 389-394.

17.

Clarke CJ , Hales A. , Hunt A. , Foxwell BM IL-10-mediated suppression of TNF-alpha production is independent of its ability to inhibit NF-kappaB activity. Eur J Immunol 1998; 28: 1719-1726.

18.

Denys A. , Udalova IA , Smith C. et al. Evidence for a dual mechanism for IL-10 suppression of TNF-alpha production that does not involve inhibition of p38 mitogen-activated protein kinase or NF-kappaB in primary human macrophages. J Immunol 2002; 168: 4837-4845.

19.

Kuwata H. , Watanabe Y. , Miyoshi H. et al. IL-10-inducible Bcl-3 negatively regulates LPS-induced TNF-alpha production in macrophages. Blood 2003; 102: 4123-4129.

20.

Williams L. , Bradley L. , Smith A. , Foxwell B. Signal transducer and activator of transcription 3 is the dominant mediator of the anti-inflammatory effects of IL-10 in human macrophages. J Immunol 2004; 172: 567-576.

21.

Berlato C. , Cassatella MA , Kinjyo I. et al. Involvement of suppressor of cytokine signaling-3 as a mediator of the inhibitory effects of IL-10 on lipopolysaccharide-induced macrophage activation. J Immunol 2002; 168: 6404-6411.

22.

Baetz A. , Frey M. , Heeg K. , Dalpke AH Suppressor of cytokine signaling (SOCS) proteins indirectly regulate Toll-like receptor signaling in innate immune cells. J Biol Chem 2004; 279: 54708-54715.

23.

Weighardt H. , Kaiser-Moore S. , Vabulas RM et al. Myeloid differentiation factor 88 deficiency improves resistance against sepsis caused by polymicrobial infection. J Immunol 2002; 169: 2823-2827.

24.

Kawai T. , Adachi O. , Ogawa T. , Takeda K. , Akira S. Unresponsiveness of MyD88-deficient mice to endotoxin. Immunity 1999; 11: 115-122.

25.

Naiki Y. , Michelsen KS , Zhang W. et al. Transforming growth factor-beta differentially inhibits MyD88-dependent, but not TRAM- and TRIF-dependent, lipopolysaccharide-induced TLR4 signaling . J Biol Chem 2005; 280: 5491-5495.

26.

Lowe EL , Doherty TM , Karahashi H. , Arditi M. Ubiquitination and de-ubiquitination: role in regulation of signaling by Toll-like receptors. J Endotoxin Res 2006 ; 12: 337-345.

27.

Meylan E. , Burns K. , Hofmann K. et al. RIP1 is an essential mediator of Toll-like receptor 3-induced NF-kappaB activation. Nat Immunol 2004; 5: 503-507.