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.