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Review
. 2004 Nov;113(3):281-92.
doi: 10.1111/j.1365-2567.2004.01988.x.

Interleukin-10 suppression of myeloid cell activation--a continuing puzzle

Lynn M Williams  1 , Giuseppe Ricchetti, Usha Sarma, Timothy Smallie, Brian M J Foxwell
Affiliations
Review

Interleukin-10 suppression of myeloid cell activation--a continuing puzzle

Lynn M Williams et al. Immunology. 2004 Nov.

Abstract

Efforts to identify the signal transduction pathways used by interleukin-10 (IL-10) have resulted in limited success. The anti-inflammatory effects elicited by IL-10, and the mechanisms by which these are mediated, are still relatively unknown. Understanding the signalling mechanisms behind the suppression of cytokine expression by IL-10 could be of potential therapeutic interest. Although the consensus is that the Janus kinase, Jak1, as well as the signal transducer and activator of transcription STAT3 are central, much controversy exists about the participation and roles of many other signalling pathways targeted by IL-10. The mechanisms of cytokine suppression proposed by various groups have included transcriptional, post-transcriptional and post-translational regulation of IL-10 target genes; nevertheless no unifying model has emerged thus far. Here we would like to highlight novel findings and discuss their implications in the context of current understanding of IL-10 signalling.

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Figures

Figure 1
Figure 1
Domains and binding motifs of the IL-10 receptor family which utilize the IL-10R2 chain. Shown in this figure are the receptor complexes involved in IL-10, IL-22 and IL-26 signalling which all utilize the IL-10R2 chain as part of the active receptor complex. IL-22 binding protein (BP) is believed to act as an inhibitor of IL-22 signalling by competition for ligand binding. The human IL-10R1 and IL-20R1 chains both contain two YXXQ STAT binding motifs while IL-22R1 has four.
Figure 2
Figure 2
Signalling cascades of the LPS pathway and reported sites of IL-10 intervention. LPS activates numerous signalling cascades that are critical for the production of cytokines by macrophages. The two dominant pathways of cytokine production, the NF-κB and the p38 MAPK pathway have both been cited as being inhibited by IL-10. The NF-κB pathway has been suggested to be regulated at several levels, with IL-10 inhibiting the activation of IKK and thereby the degradation of IκB by the proteosome and also preventing the binding of the NF-κB subunits to its binding motif. Other reports have suggested IL-10 prevents translation in murine systems by inhibiting p38-MAPK. In addition 3′ UTR of the TNF-α gene was found to be critical to IL-10 activity. With the exception of JNK, the other pathways activated by LPS have also demonstrated sensitivity to the effects of IL-10. *, Suggested site of IL-10 inhibition.
Figure 3
Figure 3
IL-10, IL-22 and IL-22 receptor signalling. Binding of IL-10, IL-22 and IL-26 to their respective receptor complex results in the initiation of various signalling cascades. In all cases the JAK/STAT pathway is the primary pathway known to be activated by ligand binding. IL-10 also activates the PI-3K pathway via the binding of the IRS-2 adaptor molecule to the IL-10R complex. STAT-1 and SHP-1 have also been shown to be activated by IL-10, however, the former is only induced with IFN-γ; preincubation. IL-22 and IL-26, like IL-10, initiate the dimerization of STAT-3, however, IL-22 also activates the JNK, ERK and MAPK pathways as well as STAT1 and -5. IL-22 and -26 also activate the acute phase/pro-inflammatory responses in cells rather than de-activation of the inflammatory response.
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