title: IL4-10 Fusion Protein Is a Novel Drug to Treat Persistent Inflammatory Pain.
abstract: Chronic pain is a major clinical problem that is difficult to treat and requires novel therapies. Although most pain therapies primarily target neurons, neuroinflammatory processes characterized by spinal cord and dorsal root ganglion production of proinflammatory cytokines play an important role in persistent pain states and represent potential therapeutic targets. Anti-inflammatory cytokines are attractive candidates to regulate aberrant neuroinflammatory processes, but the therapeutic potential of these cytokines as stand-alone drugs is limited. Their optimal function requires concerted actions with other regulatory cytokines, and their relatively small size causes rapid clearance. To overcome these limitations, we developed a fusion protein of the anti-inflammatory cytokines interleukin 4 (IL4) and IL10. The IL4-10 fusion protein is a 70 kDa glycosylated dimeric protein that retains the functional activity of both cytokine moieties. Intrathecal administration of IL4-10 dose-dependently inhibited persistent inflammatory pain in mice: three IL4-10 injections induced full resolution of inflammatory pain in two different mouse models of persistent inflammatory pain. Both cytokine moieties were required for optimal effects. The IL4-10 fusion protein was more effective than the individual cytokines or IL4 plus IL10 combination therapy and also inhibited allodynia in a mouse model of neuropathic pain. Mechanistically, IL4-10 inhibited the activity of glial cells and reduced spinal cord and dorsal root ganglion cytokine levels without affecting paw inflammation. In conclusion, we developed a novel fusion protein with improved efficacy to treat pain, compared with wild-type anti-inflammatory cytokines. The IL4-10 fusion protein has potential as a treatment for persistent inflammatory pain.
  
  
  
  The treatment of chronic pain is a major clinical and societal challenge. Current therapies to treat persistent pain states are limited and often cause major side effects. Therefore, novel analgesic treatments are urgently needed. In search of a novel drug to treat chronic pain, we developed a fusion protein consisting of two prototypic regulatory cytokines, interleukin 4 (IL4) and IL10. The work presented in this manuscript shows that this IL4-10 fusion protein overcomes some major therapeutic limitations of pain treatment with individual cytokines. The IL4-10 fusion protein induces full resolution of persistent inflammatory pain in two different mouse models. These novel findings are significant, as they highlight the IL4-10 fusion protein as a long-needed potential new drug to stop persistent pain states.
authors.affiliation: Laboratories of Translational Immunology and Neuroimmunology and Developmental Origins of Disease and n.eijkelkamp@umcutrecht.nl.
authors.forename: Niels
authors.identifier: 0000-0003-0039-7063
authors.initials: N
authors.lastname: Eijkelkamp
authors.affiliation: Laboratories of Translational Immunology and.
authors.forename: Cristine
authors.initials: C
authors.lastname: Steen-Louws
authors.affiliation: Laboratories of Translational Immunology and.
authors.forename: Sarita A Y
authors.initials: SA
authors.lastname: Hartgring
authors.affiliation: Neuroimmunology and Developmental Origins of Disease and.
authors.forename: Hanneke L D M
authors.initials: HL
authors.lastname: Willemen
authors.affiliation: Laboratories of Translational Immunology and.
authors.forename: Judith
authors.initials: J
authors.lastname: Prado
authors.affiliation: Department of Rheumatology and Clinical Immunology, University Medical Center Utrecht, 3584 EA Utrecht, The Netherlands, and.
authors.forename: Floris P J G
authors.initials: FP
authors.lastname: Lafeber
authors.affiliation: Neuroimmunology Laboratory, Department of Symptom Research, MD Anderson Cancer Center, University of Texas, Houston, Texas 77030.
authors.forename: Cobi J
authors.identifier: 0000-0002-1928-3050
authors.initials: CJ
authors.lastname: Heijnen
authors.affiliation: Laboratories of Translational Immunology and.
authors.forename: C E
authors.initials: CE
authors.lastname: Hack
authors.affiliation: Laboratories of Translational Immunology and.
authors.forename: Joel A G
authors.initials: JA
authors.lastname: van Roon
authors.affiliation: Neuroimmunology Laboratory, Department of Symptom Research, MD Anderson Cancer Center, University of Texas, Houston, Texas 77030.
authors.forename: Annemieke
authors.initials: A
authors.lastname: Kavelaars
mesh_terms: D000700:Analgesics / Q000627:therapeutic use*; D000818:Animals; D002351:Carrageenan / Q000633:toxicity; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005260:Female; D005620:Freund's Adjuvant / Q000633:toxicity; D006801:Humans; D007249:Inflammation / Q000139:chemically induced / Q000150:complications*; D016753:Interleukin-10 / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use*; D015847:Interleukin-4 / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009437:Neuralgia / Q000188:drug therapy* / Q000209:etiology*; D009457:Neuroglia / Q000187:drug effects / Q000378:metabolism; D059408:Pain Management; D017288:Pain Threshold / Q000187:drug effects; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use; D013116:Spinal Cord / Q000166:cytology; D016896:Treatment Outcome
chemical_list: D000700:Analgesics; C508609:IL10 protein, human; C508598:IL4 protein, human; D008070:Lipopolysaccharides; D011993:Recombinant Fusion Proteins; D016753:Interleukin-10; D015847:Interleukin-4; D002351:Carrageenan; D005620:Freund's Adjuvant
keywords: anti-inflammatory cytokines; fusion protein; glia; inflammatory pain