Distinct T cell/renal tubular epithelial cell interactions define differential chemokine production: Implications for tubulointerstitial injury in chronic glomerulonephritides

Chemokines can promote interstitial fibrosis that is, in turn, a strong pre dictor of renal failure in chronic glomerulonephritides (GN), Resident rena l cells, including renal tubular epithelial cells (RTEC), represent a promi nent source of chemokine expression. Evaluating those factors responsible f or sustained chemokine production by RTEC during GN is therefore crucial. T he contribution of interstitial T cells to such expression, and in particul ar the precise mature of their interactions with RTEC, are poorly understoo d. Activated T cell/RTEC coculture induced production of high levels of mon ocyte chemoattractant protein-1 (MCP-1), RANTES, and IFN-inducible protein- ill from RTEC. Using double-chamber cultures and activated T cell plasma me mbrane preparations we demonstrated that both cell contact and soluble fact ors contributed to RTEC chemokine production, Importantly, different chemok ines exhibited distinct activation requirements, Thus; for RANTES cell cont act was essential, but not sufficient. In contrast, either soluble factors or cell contact induced MCP-1 and IFN-inducible protein-10 production, alth ough both pathways were required for a maximal response. Neutralization exp eriments identified critical roles in this process for proinflammatory cyto kines such as TNF-alpha, IL-1 beta, and IFN-gamma as well as membrane molec ules such as LFA-1, Cn40 ligand, and membrane bound TNF-alpha. Finally, che motactic bioassays of T cell/RTEC coculture supernatants demonstrated 80% r eduction of monocyte migration following MCP-1 neutralization, indicating a dominant role for this chemokine. In summary, activation of renal tubular cells by infiltrating T cells can amplify and perpetuate local inflammatory responses through chemokine production differentially mediated by soluble and cell contact-dependent factors. Recognition of this regulatory diversit y has important implications in the choice of potential therapeutic targets in GN.