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Published online before print March 2, 2004

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(Journal of Leukocyte Biology. 2004;75:777-784.)
© 2004 by Society for Leukocyte Biology

Synergistic induction of CXCL9 and CXCL11 by Toll-like receptor ligands and interferon- in fibroblasts correlates with elevated levels of CXCR3 ligands in septic arthritis synovial fluids

Paul Proost^*,1, Sara Verpoest^*, Kirsten Van de Borne^*, Evemie Schutyser^*, Sofie Struyf^*, Willy Put^*, Isabelle Ronsse^*, Bernard Grillet^,2, Ghislain Opdenakker and Jo Van Damme^*

^* Laboratories of Molecular Immunology and
Immunobiology, Rega Institute for Medical Research, Leuven, Belgium

¹ Correspondence: Laboratory of Molecular Immunology, Rega Institute, K.U.Leuven, Minderbroedersstraat 10, B-3000 Leuven, Belgium. E-mail: paul.proost{at}rega.kuleuven.ac.be

The synovial cavity constitutes the ideal stage to study the interplay between microbial Toll-like receptor (TLR) ligands and cytokines. Infiltrated leukocytes and synovial fibroblasts produce cytokine- and chemokine-induced proteases for remodeling the extracellular matrix. The regulation of chemokine function for attraction and activation of leukocytes constitutes a key feature in host immunity and resolution of inflammation after infection. Enhanced levels of the CXC chemokine ligand (CXCL9)/monokine induced by interferon- (IFN-) and CXCL11/IFN-inducible T cell chemoattractant, two chemoattractants for activated T cells and natural killer cells, and ligands for CXC chemokine receptor 3 (CXCR3) were detected in the synovial fluid of septic arthritis compared with osteo- and crystal arthritis patients. In vitro, IFN- and TLR3 ligation by double-stranded RNA (dsRNA) induced the expression of CXCL9 and CXCL11 in leukocytes and skin-muscle fibroblasts, whereas ligation of TLR2, TLR4, TLR5, and TLR9 by peptidoglycan (PGN), lipopolysaccharide (LPS), flagellin, and unmethylated CpG oligonucleotides, respectively, did not. PGN and LPS, but not unmethylated CpG oligonucleotides, even inhibited IFN--induced CXCL9 and CXCL11 expression in leukocytes. In sharp contrast, in fibroblasts, the TLR ligands PGN, dsRNA, LPS, and flagellin synergized with IFN- for the production of CXCL9 and CXCL11. Although TLR ligands stimulate leukocytes to produce CXCL8/interleukin-8 during the early innate defense, they contribute less to the production of CXCR3 ligands, whereas fibroblasts are important sources of CXCR3 ligands. These results illustrate the complex interaction between cytokines and TLR ligands in infection.

Key Words: chemokine • LPS • peptidoglycan • double-stranded RNA • leukocyte

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