IL10 negatively regulates extracellular inflammatory mediators

Stable Identifier
R-HSA-6784160
Type
Reaction [BlackBoxEvent]
Species
Homo sapiens
Compartment
Locations in the PathwayBrowser
Summation

IL10 modulates the expression of cytokines, soluble mediators and cell surface molecules by cells of myeloid origin, with important consequences for their ability to activate and sustain immune and inflammatory responses. The effects of IL10 on cytokine production and function of human macrophages are generally similar to those on monocytes, although less pronounced (Moore et al. 2001). IL10 inhibits production of Interleukin-1 alpha (IL1A), IL1B, IL6, IL12, IL18, CSF2 (GM-CSF), CSF3 (G-CSF), CSF1 (M-CSF), TNF, LIF, PAF and itself by activated monocytes/macrophages (de Waal Malefyt et al. 1991, 1993, Fiorentino et al. 1991, D'Andrea et al. 1993, Gruber et al. 1994). The effect of IL10 on IL-1 and TNF production is particularly important as these cytokines often have synergistic effects on inflammatory processes, amplifying their effect by inducing secondary mediators such as chemokines, prostaglandins and PAF. IL10 also inhibits activated monocyte production of inducible chemokines that are involved in inflammation, namely CCL2 (MCP1), Ccl12 (MCP-5, in mice), CCL3, CCL3L1 (Mip-1alpha), CCL4 (Mip-1beta), CCL20 (Mip-3alpha), CCL19 (Mip-3beta), CCL5 (Rantes), CCL22 (MDC), CXCL8 (IL-8), CXCL10 (IP-10), CXCL2 (MIP-2) and CXCL1 (KC, Gro-alpha) (Berkman et al. 1995, Rossi et al. 1997, Marfaing-Koka et al. 1996, Kopydlowski et al. 1999). These are involved in the recruitment of monocytes, dendritic cells, neutrophils, and T cells, and affect both Th1 and Th2 responses. CXCL1 is induced by IFNgamma and attracts Th1 cells; CCL22 is induced by IL-4 and attracts Th2 cells.

IL10 inhibits expression of IL1R1 and IL-1RII (de Waal Malefyt et al. 1991, Jenkins et al. 1994, Dickensheets & Donnelly 1997).

Both transcriptional and posttranscriptional mechanisms have been implicated in the inhibitory effects of IL10 on cytokine and chemokine production (Bogdan et al. 1991, Clarke et al. 1998, Brown et al. 1996). IL10 regulates production of certain cytokines, such as CXCL1, by destabilizing mRNA via AU-rich elements in the 3'-UTR of sensitive genes (Kim et al. 1998, Kishore et al. 1999). IL-10 also enhances IL-1RA expression via inhibition of mRNA degradation (Cassatella et al. 1994).

IL10 indirectly inhibits production of prostaglandin E2 (PGE2) by downregulating PTGS2 (cyclooxygenase 2) expression (Niiro et al. 1994, 1995, Mertz et al. 1994), which also reduces expression of Matrix metalloproteinase 2 (MMP2) and MMP9, thereby modulating extracellular matrix turnover.

Literature References
PubMed ID Title Journal Year
1940369 IL-10 inhibits cytokine production by activated macrophages J. Immunol. 1991
8301137 Macrophage-colony-stimulating factor expression by anti-CD45 stimulated human monocytes is transcriptionally up-regulated by IL-1 beta and inhibited by IL-4 and IL-10 J. Immunol. 1994
9550426 IFN-gamma and IL-10 inhibit induction of IL-1 receptor type I and type II gene expression by IL-4 and IL-13 in human monocytes J. Immunol. 1997
7594602 Inhibition of macrophage inflammatory protein-1 alpha expression by IL-10. Differential sensitivities in human blood monocytes and alveolar macrophages J. Immunol. 1995
7902377 Effects of IL-13 on phenotype, cytokine production, and cytotoxic function of human monocytes. Comparison with IL-4 and modulation by IFN-gamma or IL-10 J. Immunol. 1993
8102388 Interleukin 10 (IL-10) inhibits human lymphocyte interferon gamma-production by suppressing natural killer cell stimulatory factor/IL-12 synthesis in accessory cells J. Exp. Med. 1993
10415057 Regulation of macrophage chemokine expression by lipopolysaccharide in vitro and in vivo J. Immunol. 1999
8921438 Contrasting effects of IL-4, IL-10 and corticosteroids on RANTES production by human monocytes Int. Immunol. 1996
1940799 Interleukin 10(IL-10) inhibits cytokine synthesis by human monocytes: an autoregulatory role of IL-10 produced by monocytes J. Exp. Med. 1991
8186324 The effects of interleukin-10 on interleukin-1 receptor antagonist and interleukin-1 beta production in human monocytes and neutrophils Lymphokine Cytokine Res. 1994
9013939 Identification through bioinformatics of two new macrophage proinflammatory human chemokines: MIP-3alpha and MIP-3beta J. Immunol. 1997
Participants
Participant Of
This entity is regulated by