title: Spinal interleukin-33 and its receptor ST2 contribute to bone cancer-induced pain in mice.
abstract: Cancer pain, particularly bone cancer pain, affects the quality of life of cancer patients, and current treatments are limited. Interleukin (IL)-33, a new member of the IL-1 super family, has been reported to be involved in the modulation of inflammatory pain. However, studies focused on its role in the modulation of cancer pain have been rare. The present study was designed to investigate whether spinal IL-33/ST2 signaling was involved in bone cancer-induced pain in mice. Bone cancer was induced via intra-femoral inoculation of 4T1 mammary carcinoma cells. The mice inoculated with carcinoma cells showed mechanical allodynia, heat hyperalgesia and a reduction in limb use, whereas phosphate-buffered saline or heat-killed cells-injected mice showed no significant difference compared to non-treated mice. The pain hypersensitive behaviors worsened over time and with bone destruction. Both the mRNA and the protein levels of IL-33 and relative cytokines (IL-1β, IL-6, TNF-a) were significantly increased in the spinal cord after the inoculation of carcinoma cells. Intrathecal administration of ST2 antibody to block IL-33/ST2 signaling alleviated pain behaviors in a dose-dependent manner in bone cancer pain mice compared with vehicle-injected mice. Moreover, the ST2(-/-) mice showed a significant amelioration of limb use and heat hyperalgesia compared to wild-type mice. Meanwhile, concentrations of spinal IL-1β, IL-6 and TNF-a in the cancer-bearing ST2(-/-) mice had no significant changes. These data further suggested that IL-33/ST2 signaling played a vital role in cancer pain. Our results provided evidence that IL-33 and its receptor ST2 may be a potential therapeutic target for the treatment of pain in bone cancer patients.
authors.affiliation: Department of Integrative Medicine and Neurobiology, School of Basic Medical Sciences, Shanghai Medical College, Institute of Acupuncture Research, Institutes of Brain Science, State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai, China.
authors.forename: J
authors.initials: J
authors.lastname: Zhao
authors.forename: H
authors.initials: H
authors.lastname: Zhang
authors.forename: S-B
authors.initials: SB
authors.lastname: Liu
authors.forename: P
authors.initials: P
authors.lastname: Han
authors.forename: S
authors.initials: S
authors.lastname: Hu
authors.forename: Q
authors.initials: Q
authors.lastname: Li
authors.forename: Z-F
authors.initials: ZF
authors.lastname: Wang
authors.forename: Q-L
authors.initials: QL
authors.lastname: Mao-Ying
authors.forename: H-M
authors.initials: HM
authors.lastname: Chen
authors.forename: J-W
authors.initials: JW
authors.lastname: Jiang
authors.forename: G-C
authors.initials: GC
authors.lastname: Wu
authors.forename: W-L
authors.initials: WL
authors.lastname: Mi
authors.forename: Y-Q
authors.initials: YQ
authors.lastname: Wang
mesh_terms: D000818:Animals; D001859:Bone Neoplasms / Q000150:complications*; D001842:Bone and Bones / Q000000981:diagnostic imaging / Q000473:pathology; D002277:Carcinoma / Q000150:complications; D045744:Cell Line, Tumor / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D006930:Hyperalgesia / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D007074:Immunoglobulin G / Q000627:therapeutic use; D000072179:Interleukin-1 Receptor-Like 1 Protein; D000067596:Interleukin-33; D007378:Interleukins / Q000276:immunology / Q000378:metabolism*; D008124:Locomotion / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D010146:Pain / Q000188:drug therapy / Q000209:etiology* / Q000473:pathology*; D010147:Pain Measurement; D011859:Radiography; D018123:Receptors, Interleukin / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D013116:Spinal Cord / Q000378:metabolism*; D013997:Time Factors
chemical_list: C486189:Il1rl1 protein, mouse; C506535:Il33 protein, mouse; D007074:Immunoglobulin G; D000072179:Interleukin-1 Receptor-Like 1 Protein; D000067596:Interleukin-33; D007378:Interleukins; D018123:Receptors, Interleukin
keywords: ERK; GFAP; HRP; IL; PBS; PWL; PWT; ST2; T helper; Th; WT; bone cancer-induced pain; extracellular signal-regulated kinase; glial fibrillary acidic protein; horseradish peroxidase; interleukin; interleukin-33; p-p38MAPK; paw withdrawal mechanical threshold; paw withdrawal thermal latency; phosphate-buffered saline; phosphorylated-p38MAPK; proinflammatory cytokines; spinal cord; wild-type