Immunology and Pathology

Interleukin-17 and CD40-Ligand Synergistically Enhance Cytokine and Chemokine Production by Renal Epithelial Cells

WOLTMAN, ANDREA M.^*; DE HAIJ, SIMONE^*; BOONSTRA, JOKE G.^*; GOBIN, SAM J.P.^†; DAHA, MOHAMED R.^*; KOOTEN, CEES VAN^*

^*Department of Nephrology, Leiden University Medical Center, Leiden, The Netherlands.

^†Department of Immunohematology and Blood Bank, Leiden University Medical Center, Leiden, The Netherlands.

Correspondence to Dr. Cees van Kooten, Department of Nephrology, Leiden University Medical Center, Building 1, C3P, Albinusdreef 2, 2333 ZA Leiden, The Netherlands. Phone: 31 71 526 3964; Fax: 31 71 524 8118; E-mail: [email protected]

Accepted March 28, 2000

Received September 8, 1999

Journal of the American Society of Nephrology 11(11):p 2044-2055, November 2000. | DOI: 10.1681/ASN.V11112044

Abstract

Renal allograft rejection is characterized by an influx of inflammatory cells. Interaction between infiltrating T cells and resident parenchymal cells might play an important role in the ongoing inflammatory response. The present study demonstrates that CD40L, a product of activated T cells, is locally expressed in kidneys undergoing rejection. Furthermore, during rejection, CD40 expression not only is present on most graft infiltrating cells but also is increased on resident tubular epithelial cells (TEC). To obtain more detailed insight in the consequences of T cell/TEC interaction, we analyzed the production of chemokines, including interleukin-8 (IL-8), monocyte chemoattractant protein-1 (MCP-1) and regulated upon activation, normal T cell expressed and secreted (RANTES), and the production of IL-6 by cultured human primary TEC in response to activation with CD40L in vitro. In addition, we studied the interaction with IL-17, a T-cell—specific cytokine previously demonstrated to be present during renal allograft rejection. The results, obtained by enzyme-linked immunosorbent assay, indicate that simultaneous activation of TEC with IL-17 and CD40L synergistically enhances production of IL-6 (2.1-fold higher than sum of single stimulations) and the chemokines IL-8 (15-fold) and RANTES (5.8-fold) as demonstrated by statistical analysis (P < 0.05), whereas effects on MCP-1 (1.4-fold) are additive. Part of the synergy can be explained by increased CD40 expression on TEC upon IL-17 stimulation. The synergy is not unique for TEC, because similar responses were found with human synoviocytes and a foreskin fibroblast cell line (FS4). Stimulation of TEC with CD40L results in activation of NF-κB and induction of cytokine production by IL-17 and CD40L is prevented by addition of the NF-κB inhibitor pyrrolidine dithiocarbamate. These data suggest an important role for T cells in renal allograft rejection by acting on parenchymal cells via both soluble mediators and direct cellular contact.