title: Inflammatory response in human skeletal muscle cells: CXCL10 as a potential therapeutic target.
abstract: Inflammatory myopathies (IMs) are systemic diseases characterized by a T helper (Th) 1 type inflammatory response and cell infiltrates within skeletal muscles. The mainstay of treatment is drugs aimed at suppressing the immune system - corticosteroids and immunosuppressants. About 25% of patients are non-responders. Skeletal muscle cells seem actively involved in the immune-inflammatory response and not only a target; understanding the molecular bases of IMs might help drug development strategies. Within muscles the interaction between the chemokine interferon (IFN)γ inducible 10 kDa protein, CXCL10 or IP-10, and its specific receptor CXCR3, present on Th1 type infiltrating cells, likely plays a pivotal role, potentially offering the opportunity for therapeutic intervention. We aimed to clarify the involvement of human skeletal muscle cells in inflammatory processes in terms of CXCL10 secretion, to elucidate the engaged molecular mechanism(s) and, finally, to evaluate muscular cell responses, if any, to some immunosuppressants routinely used in IM treatment, such as methylprednisolone, methotrexate, cyclosporin A and Infliximab. We first isolated and characterized human fetal skeletal muscle cells (Hfsmc), which expressed the specific lineage markers and showed the competence to react in the context of an in vitro alloresponse. CXCL10 protein secretion by Hfsmc was similarly induced by the inflammatory cytokines interferon (IFN)γ and tumor necrosis factor (TNF)α, above undetectable control levels, through the activation of Stat1 and NF-kB pathways, respectively; CXCL10 secretion was significantly magnified by cytokine combination, and this synergy was associated to a significant up-regulation of TNFαRII; cytokine-induced CXCL10 secretion was considerably affected only by Infliximab. Our data suggested that human skeletal muscle cells might actively self-promote muscular inflammation by eliciting CXCL10 secretion, which is known to amplify Th1 cell tissue infiltration in vivo. In conclusion, we sustain that pharmacological targeting of CXCL10 within muscular cells might contribute to keep in control pro-Th1 polarization of the immune/inflammatory response.
authors.affiliation: Department of Health Sciences, University of Rome Foro Italico, 00135 Rome, Italy. clara.crescioli@uniroma4.it
authors.forename: Clara
authors.initials: C
authors.lastname: Crescioli
authors.forename: Mariangela
authors.initials: M
authors.lastname: Sottili
authors.forename: Paolo
authors.initials: P
authors.lastname: Bonini
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Cosmi
authors.forename: Paola
authors.initials: P
authors.lastname: Chiarugi
authors.forename: Paola
authors.initials: P
authors.lastname: Romagnani
authors.forename: Gabriella B
authors.initials: GB
authors.lastname: Vannelli
authors.forename: Marta
authors.initials: M
authors.lastname: Colletti
authors.forename: Andrea M
authors.initials: AM
authors.lastname: Isidori
authors.forename: Mario
authors.initials: M
authors.lastname: Serio
authors.forename: Andrea
authors.initials: A
authors.lastname: Lenzi
authors.forename: Luigi
authors.initials: L
authors.lastname: Di Luigi
mesh_terms: D000911:Antibodies, Monoclonal / Q000494:pharmacology; D002478:Cells, Cultured; D054357:Chemokine CXCL10 / Q000276:immunology / Q000378:metabolism*; D016572:Cyclosporine / Q000494:pharmacology; D005333:Fetus; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D000069285:Infliximab; D007371:Interferon-gamma / Q000494:pharmacology; D008213:Lymphocyte Activation; D008775:Methylprednisolone / Q000494:pharmacology; D032342:Muscle Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D009220:Myositis / Q000276:immunology / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D054367:Receptors, CXCR3 / Q000276:immunology / Q000378:metabolism*; D050794:STAT1 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D018417:Th1 Cells / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D000911:Antibodies, Monoclonal; C114753:CXCL10 protein, human; C515187:CXCR3 protein, human; D054357:Chemokine CXCL10; D007166:Immunosuppressive Agents; D016328:NF-kappa B; D054367:Receptors, CXCR3; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D016572:Cyclosporine; D000069285:Infliximab; D008775:Methylprednisolone