Interleukin (IL)-10 Inhibits Nuclear Factor кB (NFкB) Activation in Human Monocytes

Abstract

Our previous studies in human monocytes have demonstrated that interleukin (IL)-10 inhibits lipopolysaccharide (LPS)-stimulated production of inflammatory cytokines, IL-1 beta, IL-6, IL-8, and tumor necrosis factor (TNF)-alpha by blocking gene transcription. Using electrophoretic mobility shift assays (EMSA), we now show that, in monocytes stimulated with LPS or TNF alpha, IL-10 inhibits nuclear stimulation of nuclear factor kappa B (NF kappa B), a transcription factor involved in the expression of inflammatory cytokine genes. Several other transcription factors including NF-IL-6, AP-1, AP-2, GR, CREB, Oct-1, and Sp-1 are not affected by IL-10. This selective inhibition by IL-10 of NF kappa B activation occurs rapidly and in a dose-dependent manner and correlates well with IL-10's cytokine synthesis inhibitory activity in terms of both kinetics and dose responsiveness. Furthermore, compounds such as tosylphenylalanyl chloromethyl ketone and pyrrolidinedithiocarbamate that are known to selectively inhibit NF kappa B activation block cytokine gene transcription in LPS-stimulated monocytes. Taken together, these results suggest that inhibition of NF kappa B activation may be an important mechanism for IL-10 suppression of cytokine gene transcription in human monocytes. IL-4, another cytokine that inhibits cytokine mRNA accumulation in monocytes, shows little inhibitory effect on LPS-induced NF kappa B activation. Further examination reveals that, unlike IL-10, IL-4 enhances mRNA degradation and does not suppress cytokine gene transcription. These data indicate that IL-10 and IL-4 inhibit cytokine production by different mechanisms.

Mechanism of inhibition of LPS-induced IL-12p40 production by IL-10 and TGF-β in ANA-1 cells

“…A NF-B binding site in murine IL-12p40 gene promoter region has been identified and is thought to play an important role in the regulation of IL-12p40 gene expression [35,36]. One earlier study has shown IL-10 to inhibit LPS-induced NF-B activation [33], however, a causal effect of IL-10 on NF-B activation and IL-12p40 gene transcription is not fully understood. One recent study showed that TGF-␤ inhibited IL-12p40 mRNA accumulation in LPS-stimulated peripheral human mononuclear cells, however, the mechanism of action of TGF-␤ on IL-12 production was not identified [37].…”

“…LPS activates a number of nuclear factors including NF-B, ets, AP-1, AP-2, GR, CREB, OCT-1, and Sp-1 [33,34]. A NF-B binding site in murine IL-12p40 gene promoter region has been identified and is thought to play an important role in the regulation of IL-12p40 gene expression [35,36].…”

Suppression of lipopolysaccharide-induced antiviral transcription factor (STAT-1 and NF-κB) complexes by antibody-dependent enhancement of macrophage infection by Ross River virus

“…Furthermore, IL-10 is a potent immunosuppressive molecule that can mediate the down-regulation of Th1 responses by inhibiting the production of IL-12, IFN-␥, and TNF-␣ (18). IL-10 is capable of inhibiting NF-B activation in human monocytes as well as IFN-␣-and IFN-␥-induced genes by suppressing tyrosine phosphorylation of STAT-1 (18,33,34). Studies with other alphaviruses have considered the expression of IL-10 p.i.…”

Cyclic AMP Modulates the Functional Plasticity of Immature Dendritic Cells by Inhibiting Src-like Kinases through Protein Kinase A-mediated Signaling

“…Similarly, the inhibition of NF-B translocation to the nucleus with an inhibitory peptide was shown to decrease the upregulation of HLA-DR, as well as that of CD80, CD83, and CD86 (39). It has been shown that the inhibitory effect exerted by IL-10 and vitamin D 3 analogs on IL-12 synthesis depends on their capability to interfere with the NF-B pathway (39,40). FIG.…”