Chemokines usage by tubular epithelial cells in IgA nephropathy: role of TNF-α and Angiotensin II

Abstract

BACKGROUND: Tubulointerstitial infiltration of immunocompetent cells is associated with a rapid progression in IgA nephropathy (IgAN). We examined the role of tumor necrosis factor-α (TNF-α) and angiotensin II (AngII) in tubular chemokines usage in IgAN. METHODS: Using a transwell co-culture system, we studied the chemokines usage and chemotactic responses of peripheral blood mononuclear cells (PBMC) towards proximal tubular epithelial cells (PTEC) following activation by conditioned medium prepared from mesangial cells cultured with IgA from IgAN patients (IgA-medium; n=45) and healthy subjects (n=30). RESULTS: Increased expression of chemokines, including CXCL1, CXCL2, CXCL8, CCL2, CCL5 and CCL11, was observed in PTEC cultured with IgA-medium. In response to IgA-medium, chemotaxis of CD45+ PBMC, and in particular, the activated GMP- 17+, CD3+ lymphocytes and CD14+ monocytes towards PTEC were increased. The transmigrated subsets exhibited differential up-regulated expression of CXCR2, CCR2 and CCR5. Chemotactic response of activated CD3+ cells was attenuated by anti-CCL5, followed by anti-CCL2 but not by anti-CXCL1 or anti-CXCL2. Transmigrated activated CD14+ cells was reduced by anti-CCL2, anti-CCL5 and anti-CXCL2. Transmigrated activated GMP-17+ was inhibited by anti-CCL5. Under all circumstances, anti-CCL11 have no effect on the cellular transmigration. PTEC activated by IgA-medium had elevated expression of AngII, transforming growth factor-β (TGF-β) and TNF-α. The release of CXCL1, CXCL2, CXCL8, CCL2, CCL5 and CCL11, was increased by TNF-α, but not by TGF-β. AngII priming further increase all chemokines examined. Synthesis of chemokines and transmigration after activation of PTEC with IgA-medium was blocked by anti-TNF-α or losartan, but not by anti-TGF-β or PD123319 (AT2R blocker). Interestingly, TGF-β blockage enhanced the apoptosis of transmigrated GMP17+ subset. CONCLUSIONS: Our data show the differential chemotactic responses of PBMC subsets towards PTEC in IgAN. These events utilize different chemokine-chemokine receptor axes and are tightly regulated through the interaction of IgA-medium induced TNF-α and AngII.