Interleukin‐10 suppression of myeloid cell activation — a continuing puzzle

Abstract

SUMMARYEfforts 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.

Recognition of Staphylococcus aureus-derived peptidoglycan (PGN) but not intact bacteria is mediated by CD14 in microglia

“…These findings suggest that under normal conditions, TLR2 and CD14 may serve to regulate IL-12 p40 release by inducing suppressor cytokines and/or activating a direct suppressor pathway. Candidate molecules may include IL-10 and/or the suppressors of cytokine signaling (SOCS) proteins (Alexander and Hilton, 2004;Elliott and Johnston, 2004;Williams et al, 2004), possibilities that are currently under investigation in our laboratory.…”

Anti-inflammatory functions of glucocorticoid-induced genes

“…IL-10 is a pleiotropic anti-inflammatory and immunomodulatory cytokine, which is expressed by several haematopoietic cell types (Grutz, 2005;Williams et al, 2004). Induction of IL-10 expression has been suggested to contribute to the anti-inflammatory properties of GCs in rheumatoid arthritis (Verhoef et al, 1999), asthma (Karagiannidis et al, 2004;Stelmach et al, 2002), multiple sclerosis (Gayo et al, 1998) and cardiac bypass surgery (Tabardel et al, 1996).…”

General Nature of the STAT3-Activated Anti-Inflammatory Response

“…The role of IL-10 in blocking inflammation through the selective reduction of expression of a wide range of mediators can be defined as an endogenous anti-inflammatory response (AIR) 3 necessary to protect the body from excessive inflammation. The anti-inflammatory effects of IL-10 are essential: while conventionally housed mice lacking IL-10 have a chronic inflammatory disease of the intestines, they also exhibit profound, and often lethal, proinflammatory phenotypes when infected with pathogens that generate acute inflammatory responses (1,3). The absence of IL-10 leads to runaway or chronic inflammation depending on the disease context, and the excessive inflammation correlates with greatly increased levels of cytokines and chemokines.…”

“…In vitro and in vivo studies have established that the primary role of IL-10 is to inhibit the powerful stimulatory effects of TLR agonists such as LPS that act on macrophages and dendritic cells (1). The central molecular effect of IL-10 is to block the production of multiple inflammatory mediators, including cytokines, chemokines, and cell surface molecules crucial for the promotion of inflammation (2).…”