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The Chemokines CXCL9, CXCL10, and CXCL11 Differentially Stimulate G_i-Independent Signaling and Actin Responses in Human Intestinal Myofibroblasts¹

Andreas Kouroumalis^*, Robert J. Nibbs, Herve Aptel^*, Karen L. Wright^*, George Kolios and Stephen G. Ward^2,*

^* Department of Pharmacy and Pharmacology, University of Bath, Bath and North East Somerset, United Kingdom; Division of Immunology, Infection and Inflammation, Western Infirmary, University of Glasgow, Glasgow, United Kingdom; and Department of Gastroenterology, Faculty of Medicine, University of Crete, Crete, Greece

Intestinal myofibroblasts have been implicated in the pathogenesis of chronic inflammatory conditions such as Crohn’s disease via interactions with an elaborate network of cytokines, growth factors, and other inflammatory mediators. CXCR3 is a G_i protein-coupled receptor that binds the proinflammatory chemokines CXCL9, CXCL10, and CXCL11, which are released from the intestinal epithelium. The three CXCR3 ligands shared the ability to activate biochemical (e.g., PI3K and MAPK activation) and functional events (actin reorganization) in intestinal myofibroblasts. However, CXCL11 is unique in its ability to elevate intracellular calcium. Surprisingly, although CXCR3 mRNA is detectable in these myofibroblasts, there is no detectable surface expression of CXCR3. Furthermore, the biochemical responses and actin reorganization stimulated by the CXCR3 ligands in intestinal myofibroblasts are insensitive to the G_i inhibitor, pertussis toxin. This suggests either the existence of differential receptor coupling mechanisms in myofibroblasts for CXCR3 that are distinct from those observed in PBLs and/or that these cells express a modified or variant CXCR3 compared with the CXCR3 expressed on PBLs.

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