The inhibitory effect of interleukin-10 (IL-10), an anti-inflammatory cytokine, on lipopolysaccharide (LPS)-induced IL-6 production was characterized by simultaneous stimulation of RAW 264.7 cells with LPS and IL-10. The presence of IL-10 significantly inhibited LPS-induced IL-6 production at a transcriptional level. The expression of IκB-ζ, which promotes IL-6 production, was induced in response to LPS and it was definitely suppressed in the presence of IL-10. Further, IL-10 inhibited LPS-induced NF-κB activation. A pharmacological inhibitor of NF-κB prevented LPS-induced IκB-ζ expression, suggesting that IL-10 might inhibit LPS-induced IκB-ζ expression via the inactivation of NF-κB. In LPS- and IL-10-stimulated cells, the expression of Bcl-3 that inhibits NF-κB activation was significantly augmented. Introduction of Bcl-3 siRNA abolished IL-10-mediated IκB-ζ inhibition. In the presence of Bcl-3, siRNA IL-10 failed to inhibit LPS-induced IL-6 production. Therefore, it was suggested that Bcl-3 induced by IL-10 might reduce LPS-induced IκB-ζ activity via inactivation of NF-κB and that reduced IκB-ζ activity failed to promote LPS-induced IL-6 production.
Moore KW, de Waal Malefyt R., Coffman RL, O'Garra A.Interleukin-10 and the interleukin-10 receptor. Annu Rev Immunol2001; 19: 683-765.
2.
Donnelly RP, Freeman SL, Hayes MPInhibition of IL-10 expression by IFN-gamma up-regulates transcription of TNF-alpha in human monocytes. J Immunol1995 ; 155: 1420-1427.
3.
Bogdan C., Paik J., Vodovotz Y., Nathan C.Contrasting mechanisms for suppression of macrophage cytokine release by transforming growth factor-beta and interleukin-10. J Biol Chem1992; 267: 23301-23308.
4.
Schottelius AJ, Mayo MW, Sartor RB, Baldwin Jr ASInterleukin-10 signaling blocks inhibitor of kappaB kinase activity and nuclear factor kappaB DNA binding . J Biol Chem1999; 274: 31868-31874.
5.
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 Immunol2004; 172: 567-576.
6.
Wang P., Wu P., Siegel MI, Egan RW, Billah MMInterleukin (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 Chem1995; 270: 9558-9563.
7.
Kontoyiannis D., Kotlyarov A., Carballo E. et al. Interleukin-10 targets p38 MAPK to modulate ARE-dependent TNF mRNA translation and limit intestinal pathology . EMBO J2001; 20: 3760-3770.
8.
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 Chem2006; 281: 6316-6324.
9.
Berlato C., Cassatella MA, Kinjyo I., Gatto L., Yoshimura A., Bazzoni F.Involvement of suppressor of cytokine signaling-3 as a mediator of the inhibitory effects of IL-10 on lipopolysaccharide-induced macrophage activation . J Immunol2002; 168: 6404-6411.
10.
Wessells J. , Baer M., Young HA et al. BCL-3 and NF-kappaB p50 attenuate lipopolysaccharide-induced inflammatory responses in macrophages . J Biol Chem2004; 279: 49995-50003.
11.
Akira S., Taga T., Kishimoto T.Interleukin-6 in biology and medicine. Adv Immunol1993; 54: 1-78.
12.
O'Neill LAHow Toll-like receptors signal: what we know and what we don't know. Curr Opin Immunol2006; 18: 3-9.
Beutler B.Inferences, questions and possibilities in Toll-like receptor signaling . Nature2004; 430: 257-263.
15.
Kitamura H. , Kanehira K., Shiina T. et al. Bacterial lipopolysaccharide induces mRNA expression of an IkappaB MAIL through Toll-like receptor 4. J Vet Med Sci2002; 64: 419-422.
16.
Yamamoto M. , Yamazaki S., Uematsu S. et al. Regulation of Toll/IL-1-receptor mediated gene expression by the inducible nuclear protein IkappaBzeta. Nature2004; 430: 218-222.
17.
Kitamura H., Kanehira K., Okita K., Morimatsu M., Saito M.MAIL, a novel nuclear I kappa B protein that potentiates LPS-induced IL-6 production. FEBS Lett2000; 485: 53-56.
18.
Yamazaki S., Muta T., Matsuo S., Takeshige K.Stimulus-specific induction of a novel nuclear factor-kappaB regulator, IkappaB-zeta, via Toll/interleukin-1 receptor is mediated by mRNA stabilization . J Biol Chem2005; 280: 1678-1687.
19.
Trinh DV, Zhu N., Farhang G., Kim BJ, Huxford T.The nuclear I kappaB protein I kappaB zeta specifically binds NF-kappaB p50 homodimers and forms a ternary complex on kappaB DNA. J Mol Biol2008; 379: 122-135.
20.
Dagvadorj J. , Naiki Y., Tumurkhuu G. et al. Interleukin-10 inhibits tumor necrosis factor-alpha production in lipopolysaccharide-stimulated RAW 264. 7 cells through reduced MyD88 expression . Innate Immun2008; 14: 109-115.
21.
Nolan GP, Fujita T., Bhatia K. et al. The bcl-3 proto-oncogene encodes a nuclear I kappa B-like molecule that preferentially interacts with NF-kappa B p50 and p52 in a phosphorylation-dependent manner. Mol Cell Biol1993; 13: 3557-3566.
22.
Turkson J., Ryan D., Kim JS et al. Phosphotyrosyl peptides block Stat3 mediated DNA binding activity, gene regulation, and cell transformation. J Biol Chem2001; 276: 45443-45455.
23.
Mühlbauer M. , Chilton PM, Mitchell TC, Jobin C.Impaired Bcl3 up-regulation leads to enhanced lipopolysaccharide-induced interleukin (IL)-23P19 gene expression in IL-10(-/-) mice. J Biol Chem2008; 283: 14182-14189.
24.
Caamaño JH, Perez P., Lira SA, Bravo R.Constitutive expression of Bc1-3 in thymocytes increases the DNA binding of NFkappaB1 (p50) homodimers in vivo. Mol Cell Biol1996; 16: 1342-1348.
25.
Yamazaki S. , Muta T., Takeshige K.A novel IkappaB protein, IkappaB-zeta, induced by proinflammatory stimuli, negatively regulates nuclear factor-kappaB in the nuclei. J Biol Chem2001; 276: 27657-27662.
26.
Totzke G., Essmann F., Pohlmann S.A novel member of the IkappaB family, human IkappaB-zeta, inhibits transactivation of p65 and its DNA binding. J Biol Chem2006 ; 281: 12645-12654.
27.
Muta T.IkappaB-zeta: an inducible regulator of nuclear factorkappaB. Vitam Horm2006; 74: 301-316.
28.
Yamamoto M. , Takeda K.Role of nuclear IkappaB proteins in the regulation of host immune responses. J Infect Chemother2008; 14: 265-269.
29.
Kuwata H., Watanabe Y., Miyoshi H. et al. IL-10-inducible Bcl-3 negatively regulates LPS-induced TNF-alpha production in macrophages. Blood2003; 102: 4123-4129.
30.
Eto A., Muta T., Yamazaki S., Takeshige K.Essential roles for NF-kappa B and a Toll/IL-1 receptor domain-specific signal(s) in the induction of I kappa B-zeta. Biochem Biophys Res Commun2003; 301: 495-501.
