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Arthritis and Rheumatism Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892
Chemokines can promote interstitial fibrosis that is, in turn, a
strong predictor of renal failure in chronic glomerulonephritides (GN).
Resident renal cells, including renal tubular epithelial cells (RTEC),
represent a prominent source of chemokine expression. Evaluating those
factors responsible for sustained chemokine production by RTEC during
GN is therefore crucial. The contribution of interstitial T cells to
such expression, and in particular the precise nature of their
interactions with RTEC, are poorly understood. Activated T cell/RTEC
coculture induced production of high levels of monocyte chemoattractant
protein-1 (MCP-1), RANTES, and IFN-inducible protein-10 from RTEC.
Using double-chamber cultures and activated T cell plasma membrane
preparations we demonstrated that both cell contact and soluble factors
contributed to RTEC chemokine production. Importantly, different
chemokines exhibited distinct activation requirements. Thus, for RANTES
cell contact was essential, but not sufficient. In contrast, either
soluble factors or cell contact induced MCP-1 and IFN-inducible
protein-10 production, although both pathways were required for a
maximal response. Neutralization experiments identified critical roles
in this process for proinflammatory cytokines such as TNF-
, IL-1ß,
and IFN-
as well as membrane molecules such as LFA-1, CD40 ligand,
and membrane bound TNF-. Finally, chemotactic bioassays of T
cell/RTEC coculture supernatants demonstrated 80% reduction 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 diversity has important implications in the choice of
potential therapeutic targets in GN.
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