title: IL-17 induces hyperalgesia via TNF-dependent neutrophil infiltration.
abstract: Interleukin-17 (IL-17) and tumour necrosis factor-α (TNF) are critical in the pathogenesis of arthritis but their relationship during inflammatory pain has received limited attention. We aimed to establish whether IL-17 can induce hyperalgesia in acute conditions, and investigated the role of TNF in mediating the pain response. Hyperalgesia was elicited in C57BL/6 mice by injection of recombinant IL-17, TNF or vehicle into the plantar tissue. Elevated pain was measured by the Hargreaves test for thermal hyperalgesia and Linton incapacitance tester for weight-bearing change. Cellular infiltration during hyperalgesia was determined by histological analysis and myeloperoxidase assay. IL-17 was found to induce hyperalgesia, but this was dependent on neutrophil migration and TNF binding to TNF receptor 1 (TNFR1). Because TNF-induced hyperalgesia was also dependent on neutrophil migration, the relationship between the resident fibroblasts, the cytokines and the migrating neutrophils was further investigated. By means of an air pouch model of cell migration, it was established that IL-17-induced neutrophil infiltration was dependent of TNF/TNFR1 as this interaction was required for the induction of the chemokine keratinocyte chemoattractant. These findings suggest that IL-17 causes acute hyperalgesia indirectly by inducing TNF from resident cells. The subsequent production of keratinocyte chemoattractant then triggers neutrophil chemotaxis to the plantar tissue, releasing algesic mediators locally to sensitise the nerve.
authors.affiliation: Kennedy Institute of Rheumatology, Imperial College London, London W6 8LH, UK Department of Somatic Pain Research, Neurology & GI Centre of Excellence for Drug Discovery, GlaxoSmithKline Research & Development Limited, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, UK Peripheral Neuropathy Unit, Hammersmith Hospital, Imperial College London, London W12 0NN, UK School of Medicine & Pharmacology, University of Western Australia, Western Australia, WA 6009, Australia.
authors.forename: Kay E
authors.initials: KE
authors.lastname: McNamee
authors.forename: Saba
authors.initials: S
authors.lastname: Alzabin
authors.forename: Jane P
authors.initials: JP
authors.lastname: Hughes
authors.forename: Praveen
authors.initials: P
authors.lastname: Anand
authors.forename: Marc
authors.initials: M
authors.lastname: Feldmann
authors.forename: Richard O
authors.initials: RO
authors.lastname: Williams
authors.forename: Julia J
authors.initials: JJ
authors.lastname: Inglis
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004797:Enzyme-Linked Immunosorbent Assay; D006930:Hyperalgesia / Q000139:chemically induced* / Q000235:genetics; D020381:Interleukin-17 / Q000009:adverse effects*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020556:Neutrophil Infiltration / Q000187:drug effects*; D017288:Pain Threshold / Q000187:drug effects*; D018124:Receptors, Tumor Necrosis Factor / Q000172:deficiency; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000172:deficiency; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000009:adverse effects / Q000378:metabolism*
chemical_list: D020381:Interleukin-17; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; C469948:Tnfrh2 protein, mouse; C506236:Tnfrsf1a protein, mouse; D014409:Tumor Necrosis Factor-alpha