Abstract
The exact function of interleukin-19 (IL-19) on immune response is poorly understood. In mice, IL-19 up-regulates TNFα and IL-6 expression and its deficiency increases susceptibility to DSS-induced colitis. In humans, IL-19 favors a Th2 response and is elevated in several diseases. We here investigate the expression and effects of IL-19 on cells from active Crohn’s disease (CD) patient. Twenty-three active CD patients and 20 healthy controls (HC) were included. mRNA and protein IL-19 levels were analyzed in monocytes. IL-19 effects were determined in vitro on the T cell phenotype and in the production of cytokines by immune cells. We observed that unstimulated and TLR-activated monocytes expressed significantly lower IL-19 mRNA in active CD patients than in HC (logFC = −1.97 unstimulated; −1.88 with Pam3CSK4; and −1.91 with FSL-1; p<0.001). These results were confirmed at protein level. Exogenous IL-19 had an anti-inflammatory effect on HC but not on CD patients. IL-19 decreased TNFα production in PBMC (850.7±75.29 pg/ml vs 2626.0±350 pg/ml; p<0.01) and increased CTLA4 expression (22.04±1.55% vs 13.98±2.05%; p<0.05) and IL-4 production (32.5±8.9 pg/ml vs 13.5±2.9 pg/ml; p<0.05) in T cells from HC. IL-10 regulated IL-19 production in both active CD patients and HC. We observed that three of the miRNAs that can modulate IL-19 mRNA expression, were up-regulated in monocytes from active CD patients. These results suggested that IL-19 had an anti-inflammatory role in this study. Defects in IL-19 expression and the lack of response to this cytokine could contribute to inflammatory mechanisms in active CD patients.
Highlights
IL-19 is mainly produced by myeloid cells, B cells and epithelial cells
In a microarray analysis of purified monocytes heterozygous for the TLR1 SNP I602S, we identified genes that were differentially down-regulated in monocytes from active Crohn’s disease (CD) patients compared to monocytes from healthy controls (HC) (53 genes in monocytes cultured with medium; 78 genes in monocytes cultured with Pam3CSK4 and 60 genes in monocytes cultured with FSL-1)
Among down-regulated genes in monocytes from active CD patients, we found IL-19, a cytokine related to the IL-10 family (Fig. 1A)
Summary
IL-19 is mainly produced by myeloid cells, B cells and epithelial cells. It can be induced by the TLR4 ligand (LPS) and granulocyte-macrophage colony-stimulating factor (GM-CSF). Expression of the IL20Ra chain has not been detected on human leukocytes to date, suggesting that immune cells are only a minor target for the effects of IL-19 [3] These results are not conclusive because other studies have shown that IL-19 enhances the production of Th2 cytokines in T cells [4] and IL-10 but not TNFa in unstimulated monocytes [5]. Ching-Hua Yeh et al reported that the serum levels of IL-19 correlate inversely with the levels of IFNc-secreted CD4+T cells after PMA/ionomycin stimulation. These authors showed that IL-19 up-regulates Foxp mRNA and induces the regulatory function of human CD4+ T cells. These results suggest that IL-19 plays an intriguing role during the immune response [7]
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