Study of Interleukin-19 in Systemic Inflammatory Diseases

• Main Authors: Chung-Hsi Hsing, 邢中熹
• Other Authors: Ming-Shi Chang
• Format: Others
• Language: en_US
• Published: 2008
• Online Access: http://ndltd.ncl.edu.tw/handle/36975689885873496038

博士 === 國立成功大學 === 藥學生物科技研究所 === 96 === Cytokines are important mediators in systemic inflammatory diseases. It is valuable while to discovery novel cytokines and to identify their functions and effects on the inflammatory diseases. IL-19 is a newly discovered proinflammatory cytokine belonging to IL-10 family. At the present time, knowledge about IL-19 on inflammatory diseases is still limited. Previous reports showed that IL-19 induced immune cells to produce IL-6, IL-8, TNF-α and ROS and undergo apoptosis. IL-19 was also involved in Th1/Th2 polarization which is related to immune regulation. Clinically, IL-19 was reported to be involved in the mechanism of chronic local inflammatory diseases such as psoriasis and asthma. In our preliminary exploration, we found that IL-19 was obviously increased in systemic inflammatory response syndrome (SIRS) after cardiac surgery with cardiopulmonary bypass (CPB). We, therefore, were interesting about the novel effects of IL-19 on acute and chronic systemic inflammatory diseases. We hypothesize that, first, the levels of IL-19 after CPB is associated with the changes of other proinflammatory cytokines which were associated with organ dysfunction after cardiac surgery. Second, IL-19 is induced in sepsis/SIRS and related to the pathogenesis of tissue injury. Third, according to the status of chronic systemic inflammation in uremic patients with hemodialysis, we hypothesize that IL-19 is altered and associated with Th1/Th2 dysregulation in uremia which may affect immunosupression in these patients. Our results showed that IL-19 was induced and associated with the production of IL-6, IL-10, and TNF-α after CPB. IL-19 transcripts in monocytes from patients were increased after CPB, which indicated that monocyte is one of the important sources of IL-19. In vitro experiments showed that IL-6 and TNF-α upregulated IL-19 protein expression in monocytes. We then survey the distribution of IL-19 in tissues and cells using immunohistochemistry study and found that skin, lung, liver and kidney were major organs expressing IL-19. Specific epithelial cells, macrophages, and endothelial cells were the major cell types stained positive for IL-19. In addition, these cells also expressed IL-19 receptors indicated that IL-19 plays an important role in these cells. In patients of severe sepsis, serum levels of IL-19 were higher in patients than in healthy volunteers. IL-19 induced apoptosis in lung epithelial cells and ROS production in liver cells in vitro. IL-19 also promoted neutrophil chemotaxis, reduced neutrophil apoptosis, and induced the production of proinflammatory cytokines and chemokines (IL-1β, IL-6, IL-8, CCL5, and CXCL9) in lung epithelial cells. In lipopolysaccharide (LPS)-challenged mice, transcripts of IL-19 and its receptors were upregulated in heart, lung, liver, and kidney tissue. Neutrophil infiltration in lung and liver tissue, and serum levels of ALT and AST, were lower in mice electroporated with IL-19 soluble receptor plasmid DNA before LPS treatment compared to control mice. These findings suggested that IL-19 plays as a detrimental role in SIRS. In uremic patients, a status of chronic systemic inflammatory disease, serum levels of IL-19 showed wide distributed amount individuals. However, IL-19 levels in the uremic patients but not in healthy controls correlated positively with both the proinflammatory cytokines (IL-6 and TNF-α) and the Th2 cytokines (IL-4, IL-5, IL-6, IL-10, and IL-13). Cultured monocytes from uremic patients with high IL-19 serum levels produced more IL-19 in vitro. In addition, uremic serum upregulated the production of IL-19 in resting monocytes. Compared with T cells from healthy controls, uremic T cells expressed more endogenous Th2 cytokine transcripts and further responded to IL-19 stimulation in Th2 cytokine production in vitro. In conclusion, serum IL-19 was induced and correlated with IL-6 and TNF-α in acute and chronic systemic inflammation. The upregulated IL-19 in endotoxic shock/sepsis was involved in lung and liver tissue injury. IL-19 also correlated with Th2 immune responses and induced Th1/Th2 cytokine dysregulation in uremia. Our findings provide a new concept that IL-19, the recent discovered cytokine, is an important molecule and might to be a potential therapeutic target in systemic inflammatory diseases.