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Immunoglobulin A (IgA) nephropathy is an important cause of end-stage kidney disease (ESKD). Tubulointerstitial inflammation and subsequent fibrosis appear to be a major contributor of the disease progression to ESKD; however, the underlying mechanism is poorly understood. Herein, we report that a unique feature of CYLD expression in kidneys of patients with IgA nephropathy and a CYLD-mediated negative regulation of inflammatory responses in human tubular epithelial cells. Immunochemical staining revealed that CYLD was predominantly expressed in renal tubular epithelial cells in 81% of the patients (37 cases) with proteinuric IgA nephropathy. Patients with positive CYLD had significantly less tubulointerstitial lesions and higher estimated glomerular filtration rate (eGFR) levels when compared with those negative. Logistic regression analysis indicated that eGFR was a predictor for the CYLD expression. In cultured human tubular epithelial HK-2 cells, tumor necrosis factor-alpha (TNFalpha) up-regulated CYLD expression. Adenoviral knockdown of CYLD did not affect albumin-, hydrogen peroxide (H(2)O(2))-, tunicamycin- or thapsigargin-induced cell death; however, it enhanced TNFalpha-induced expression of intracellular adhesion molecule (ICAM)-1 as well as activation of c-Jun N-terminal kinase (JNK). Moreover, monocyte adhesion to the TNFalpha-inflamed HK-2 cells was significantly increased by the CYLD shRNA approach. Taken together, our results suggest that CYLD negatively regulates tubulointertitial inflammatory responses via suppressing activation of JNK in tubular epithelial cells, putatively attenuating the progressive tubulointerstitial lesions in IgA nephropathy.