TWEAK (tumor necrosis factor-like weak inducer of apoptosis) is a TNF superfamily cytokine that activates the fibroblast growth factor-inducible 14 (Fn14) receptor. Transcriptional analysis of experimental kidney tubulointerstitial inflammation showed a correlation between an upregulation of the mRNA for the transmembrane chemokine CXCL16, a T-cell chemoattractant, and Fn14 activation. Exogenous TWEAK increased mouse kidney CXCL16 expression and T-lymphocyte infiltration in vivo, processes inhibited by the NF-kappa B inhibitor parthenolide. Tubular cell CXCL16 was increased in a nephrotoxic tubulointerstitial inflammation model and neutralizing anti-TWEAK antibodies decreased this CXCL16 expression and lymphocyte infiltration. In human kidney biopsies with tubulointerstitial inflammation, tubular cell CXCL16 and Fn14 expressions were associated with inflammatory infiltrates. TWEAK upregulated CXCL16 mRNA expression in cultured renal tubular cells in an NF-kappa B-dependent manner and increased soluble and cellular CXCL16 protein. CXCL16 modestly promoted the expression of cytokines in tubular cells expressing its receptor (CXCR6) and appeared to synergize with TWEAK to promote an inflammatory response; however, it did not modulate tubular cell proliferation or survival. Thus, TWEAK upregulates the expression of the chemokine CXCL16 in tubular epithelium and this may contribute to kidney tubulointerstitial inflammation. Kidney International (2012) 81, 1098-1107; doi: 10.1038/ki.2011.475; published online 25 January 2012