CXCR3 Expression and Activation of Eosinophils: Role of IFN-γ-Inducible Protein-10 and Monokine Induced by IFN-γ

Abstract

CXC chemokine receptor 3 (CXCR3), predominately expressed on memory/activated T lymphocytes, is a receptor for both IFN-γ-inducible protein-10 (γ IP-10) and monokine induced by IFN-γ (Mig). We report a novel finding that CXCR3 is also expressed on eosinophils. γ IP-10 and Mig induce eosinophil chemotaxis via CXCR3, as documented by the fact that anti-CXCR3 mAb blocks γ IP-10- and Mig-induced eosinophil chemotaxis. γ IP-10- and Mig-induced eosinophil chemotaxis are up- and down-regulated by IL-2 and IL-10, respectively. Correspondingly, CXCR3 protein and mRNA expressions in eosinophils are up- and down-regulated by IL-2 and IL-10, respectively, as detected using flow cytometry, immunocytochemical assay, and a real-time quantitative RT-PCR technique. γ IP-10 and Mig act eosinophils to induce chemotaxis via the cAMP-dependent protein kinase A signaling pathways. The fact that γ IP-10 and Mig induce an increase in intracellular calcium in eosinophils confirms that CXCR3 exists on eosinophils. Besides induction to chemotaxis, γ IP-10 and Mig also activate eosinophils to eosinophil cationic protein release. These results indicate that CXCR3-γ IP-10 and -Mig receptor-ligand pairs as well as the effects of IL-2 and IL-10 on them may be especially important in the cytokine/chemokine environment for the pathophysiologic events of allergic inflammation, including initiation, progression, and termination in the processes.

Gliadin Induces an Increase in Intestinal Permeability and Zonulin Release by Binding to the Chemokine Receptor CXCR3

“…30,31 CXCR3 is predominantly expressed on different T-cell subsets, including activated T helper cell 1 (Th1) cells, 32 T lymphocytes, 33 a newly identified E-cadherin-bearing CD8 + T-cell subset that specifically homes to the gut, 34 and natural killer cells, 35 but its expression has been reported on other cell types as well. 36,37 The phenomenon that ligands other than chemokines can bind to chemokine receptors has been reported previously; for example, human immunodeficiency virus uses the CCR5 chemokine receptor for cell entry, 38 and PGP, a peptide derived from the extracellular matrix, signals through the CXCR2 receptor on neutrophils causing neutrophil recruitment into the lungs and production of superoxide. 39…”

“…Intestinal epithelial cell lines, IEC6 (rat, passage 36-46) and CaCo-2 (human, passage [30][31][32][33][34][35][36][37][38][39][40], were grown on Lab-Tek I chamber slides and stained for CXCR3 as described above. To localize CXCR3 expression in intestinal tissues, 4-µm sections were prepared, and laser capture microdissection (mouse tissue) or immunohistochemistry (human tissue) were performed as previously described.…”

Development of Atopic Dermatitis-Like Skin Lesions in STAT6-Deficient NC/Nga Mice

“…Recently, it has been demonstrated that CXCR3, predominantly expressed on human IL-2-stimulated T cells, is a receptor for IFN-␥-inducible protein 10 (IP10) and monokine induced by IFN-␥ (Mig) (40). The induced IP10 and Mig activate eosinophils through CXCR3 that is also expressed on eosinophils (41). It would be possible that this IFN-␥-induced IP10/CXCR3 pathway plays a role in the disease site of NC mice, although we have not analyzed IP10, Mig, and CXCR3 expression in this study.…”

Regulation of Blastocyst Migration, Apposition, and Initial Adhesion by a Chemokine, Interferon γ-inducible Protein 10 kDa (IP-10), during Early Gestation

“…IP-10, belongs to the CXC chemokine subfamily, is induced in a variety of cell types (10), and regulates multiple aspects of inflammatory and immune responses primarily through chemotactic activity toward subsets of leukocytes (11). IP-10 targets the receptor CXCR3 and activates several subsets of leukocytes, NK cells, Th1 lymphocytes, eosinophils and dendritic cells (12)(13)(14)(15). Several chemo-kines have been discovered in the fetal and maternal annexes during the early pregnancy in humans (16 -18), mice (19 -21), and ruminants (7,22,23).…”