The Effects Of Th17 And Its Cytokine On Distinct Immunopathologic Characteristics Of Chronic Rhinosinusitis With Nasal Polyps

Background Chronic rhinosinusitis with nasal polyps (CRSwNP) is characterized by persistent inflammation of the nasal and paranasal mucosa, characterized with distinct stromal edema and the infiltration of large numbers of inflammatory cells, including dominant eosinophils, mast cells, lymphocytes, macrophages and plasma cells. Although a plenty of research has been made on multiple levels, its pathogenesis is still unknown. Studies from European patients showed that CRSwNP is characterized by a Th2 skewed eosinophilic inflammation with high levels of IL-5 and IgE. Some studies also found that CRSwNP is characterized by a mixed Th1/Th2 skewed cytokines response. Other than eosinophils, it has also been suggested that neutrophils play an important role in chronic inflammation of nasal polyps. Recently, it has been suggested that CRSwNP in Asians present different immunopathologic features compared with those in European patients. Zhang N et al discovered that in CRSwNP patients living in southern China demonstrated a Th1/Th17 cell pattern with a minor eosinophilic inflammation compared with Belgian patients. But, Cao PP et al found that Th2 skewed inflammation with predominant Th17 reactions can be demonstrated in eosinophilic CRSwNP. Further understanding of Th17 cells in CRSwNP will be of great value in elucidating the pathogenesis of CRSwNP.Interleukin-17A (IL-17), mainly produced by Th17 cells, was previously described as an inflammatory cytokine that induces a profile of proinfl- ammatory cytokines, chemokines and metalloproteinases. Although several reports have demonstrated that IL-17 has an important role on rheumatoid arthritis, multiplesclerosis, inflammatory bowel disease, pneumonia and asthma, it remains unclear as to whether IL-17 is involved in the pathogenesis of human nasal epithelial cells.We sought to determine the effects of Th17 and its cytokine in distinct immunopathologic characteristics of chronic rhinosinusitis with nasal polyps and the IL-17 on the proinflammatory cytokine/chemokine releases of primary cultured human nasal epithelial cells.Method On the first part, histopathological observations and immunohistochemical staining for IL-17, IL-17 receptor and CD68 were performed on 52 specimens (42 nasal polyps and 10 specimens of inferior turbinate as normal control). Double immunohistochemical staining was done to determine which cells expressed IL-17. In situ hybridization was done to determine which cells expressed IL-17 mRNA. The serum expression levels of IL-17 were determined by ELISA whilst the mRNA expression of IL-17 and Th17 cells transcription factor retinoid acid-related orphan receptor C (RORc) was determined by real-time quantitative PCR. On the second part, nasal mucosa were obtained from 27 nasal polyps and 10 specimens of inferior turbinate. After the isolation of HNEC, epithelial cells of nasal polyps and inferior turbinate were cultured without serum under stimulus of IL-17 10, 100ng/ml, IL-Iβ20ng/ml for 12h, 24h and 48h, respectively. The expression ofIL-6 and GM-CSF derived from epithelial cells were detected by ELISA. Result 42.9% of CRSwNP specimens presented eosinophilic inflame mation. Relatively higher mRNA expression levels of IL-17 and RORc were seen in CRSwNP compared to the controls. A marked increase of IL-17, IL-17 receptor and CD68 proteins (P<.01) were seen in CRSwNP group. The expression levels of IL-17 and RORc did not differ between eosinophilic and noneosinophilic CRSwNP (P>.05). However, high expression levels of IL-17 receptor were seen in noneosinophilic CRSwNP compared with eosinophilic CRSwNP (P< .05). The serum expression of IL-17 in CRSwNP patients was similar to healthy controls. The IL-17 expressing cells mainly were the macrophages and nasal epithelial cells. The IL-17 mRNA expressing cells mainly were the lymphocytes and nasal epithelial cells. The IL-17 receptor was mainly expressed in epithelial lamina basal cells, glandular tube basal cells and small vascular endothelial cells. The expression of IL-6 and GM-CSF protein was time and dose-dependent and stronger in nasal polyps epithelial cells than inferior turbinate under stimulus of IL-17.Conclusion Chinese CRSwNP patients demonstrated an enhanced Th17 response regardless of eosinophilic or noneosinophilic inflammation. IL-17 involved in the development of nasal polyps through its local immune modulation maybe through macrophages and epithelial cells. The interaction between IL-17 with IL-17 receptor might contribute to the growth of nasal polyps, such as epithelial cell basal lamina thickening and gland hyperplasia. Besides, IL-17 showed a proinflammatory effect on human nasal epithelial cells.