Expression of IFN-gamma-inducible chemokines in inclusion body myositis.
Because IFN-gamma-inducible chemokines, Mig (CXCL9), IP-10 (CXCL10), I-TAC (CXCL11) and their receptor, CXCR3, are critical molecules in T cell trafficking and generation of effector T cells, we examined their expression in the muscle biopsies of patients with sporadic inclusion body myositis (s-IBM) and disease controls. The functional role of these molecules was also studied by examining the effect and time kinetics of IFN-gamma in inducing Mig and IP-10 expression in human myotubes in vitro. We found significantly high levels of Mig and IP-10 mRNA expression in s-IBM muscles compared to controls. IFN-gamma upregulated the mRNA expression of Mig and IP-10 by human myotubes in a dose-dependent manner. By double-label immunohistochemistry, Mig was expressed on a subset of CD8(+) cells and the areas of the muscle fiber in contact or contiguous to the T cells; CXCR3 was expressed only on a subset of the autoinvasive CD8(+) T cells but not the myofibers. IP-10 and I-TAC were not detected by immunocytochemistry. The findings indicate that in s-IBM, IFN-gamma is involved in the upregulation and in situ production of proinflammatory chemokines, which, in turn, participate in the recruitment of activated T cells and contribute to the self-sustaining nature of endomysial inflammation.
Raju
Raghavanpillai
R
National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892-1382, USA.
Vasconcelos
Olavo
O
Granger
Rebekah
R
Dalakas
Marinos C
MC
D054357:Chemokine CXCL10; D054370:Chemokine CXCL9; D019743:Chemokines, CXC / Q000096:biosynthesis* / Q000235:genetics; D046508:Culture Techniques; D006801:Humans; D007150:Immunohistochemistry; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis / Q000235:genetics; D007371:Interferon-gamma / Q000494:pharmacology / Q000502:physiology*; D008024:Ligands; D018485:Muscle Fibers, Skeletal / Q000276:immunology / Q000378:metabolism; D018482:Muscle, Skeletal / Q000276:immunology / Q000378:metabolism; D018979:Myositis, Inclusion Body / Q000276:immunology*; D012333:RNA, Messenger / Q000096:biosynthesis; D054367:Receptors, CXCR3; D019707:Receptors, Chemokine / Q000096:biosynthesis / Q000235:genetics; D015854:Up-Regulation / Q000276:immunology
C080810:CXCL9 protein, human; C515187:CXCR3 protein, human; D054357:Chemokine CXCL10; D054370:Chemokine CXCL9; D019743:Chemokines, CXC; D036341:Intercellular Signaling Peptides and Proteins; D008024:Ligands; D012333:RNA, Messenger; D054367:Receptors, CXCR3; D019707:Receptors, Chemokine; D007371:Interferon-gamma