{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T05:27:38Z","timestamp":1787030858124,"version":"build-2736575974"},"reference-count":50,"publisher":"Oxford University Press (OUP)","issue":"3","license":[{"start":{"date-parts":[[2009,8,1]],"date-time":"2009-08-01T00:00:00Z","timestamp":1249084800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2009,8,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>IL-6 is crucial for the induction of many murine models of autoimmunity including experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis. To establish the role of site-specific production of IL-6 in autoimmunity, we examined myelin oligodendrocyte glycoprotein immunization-induced EAE in transgenic mice (GFAP-IL6) with IL-6 production restricted to the cerebellum. Myelin oligodendrocyte glycoprotein-immunized (Mi-) GFAP-IL6 mice developed severe ataxia but no physical signs of spinal cord involvement, which was in sharp contrast to Mi-wild type (WT) animals that developed classical EAE with ascending paralysis. Immune pathology and demyelination were nearly absent from the spinal cord, but significantly increased in the cerebellum of Mi-GFAP-IL6 mice. Tissue damage in the cerebellum in the Mi-GFAP-IL6 mice was accompanied by increased total numbers of infiltrating leukocytes and increased proportions of both neutrophils and B-cells. With the exception of IL-17 mRNA, which was elevated in both control immunized and Mi-GFAP-IL6 cerebellum, the level of other cytokine and chemokine mRNAs were comparable with Mi-WT cerebellum whereas significantly higher levels of IFN-\u03b3 and TNF-\u03b1 mRNA were found in Mi-WT spinal cord. Thus, site-specific production of IL-6 in the cerebellum redirects trafficking away from the normally preferred antigenic site the spinal cord and acts as a leukocyte \u201csink\u201d that markedly enhances the inflammatory cell accumulation and disease. The mechanisms underlying this process likely include the induction of specific chemokines, activation of microglia, and activation and loss of integrity of the blood-brain barrier present in the cerebellum of the GFAP-IL6 mice before the induction of EAE.<\/jats:p>","DOI":"10.4049\/jimmunol.0900242","type":"journal-article","created":{"date-parts":[[2009,7,13]],"date-time":"2009-07-13T21:43:38Z","timestamp":1247521418000},"page":"2079-2088","source":"Crossref","is-referenced-by-count":103,"title":["Site-Specific Production of IL-6 in the Central Nervous System Retargets and Enhances the Inflammatory Response in Experimental Autoimmune Encephalomyelitis"],"prefix":"10.1093","volume":"183","author":[{"given":"Albert","family":"Quintana","sequence":"first","affiliation":[{"name":"School of Molecular and Microbial Biosciences"},{"name":"Institute of Neurosciences and Department of Cellular Biology, Physiology and Immunology, Autonomous University Barcelona ,","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcus","family":"M\u00fcller","sequence":"additional","affiliation":[{"name":"School of Molecular and Microbial Biosciences"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ricardo F","family":"Frausto","sequence":"additional","affiliation":[{"name":"School of Molecular and Microbial Biosciences"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raquel","family":"Ramos","sequence":"additional","affiliation":[{"name":"Institute of Neurosciences and Department of Cellular Biology, Physiology and Immunology, Autonomous University Barcelona ,","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel R","family":"Getts","sequence":"additional","affiliation":[{"name":"Department of Pathology"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisenda","family":"Sanz","sequence":"additional","affiliation":[{"name":"School of Molecular and Microbial Biosciences"},{"name":"Institute of Neurosciences and Department of Cellular Biology, Physiology and Immunology, Autonomous University Barcelona ,","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Markus J","family":"Hofer","sequence":"additional","affiliation":[{"name":"School of Molecular and Microbial Biosciences"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marius","family":"Krauthausen","sequence":"additional","affiliation":[{"name":"School of Molecular and Microbial Biosciences"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicholas J C","family":"King","sequence":"additional","affiliation":[{"name":"Department of Pathology"},{"name":"Bosch Institute, University of Sydney ,","place":["Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan","family":"Hidalgo","sequence":"additional","affiliation":[{"name":"Institute of Neurosciences and Department of Cellular Biology, Physiology and Immunology, Autonomous University Barcelona ,","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Iain L","family":"Campbell","sequence":"additional","affiliation":[{"name":"School of Molecular and Microbial Biosciences"},{"name":"Bosch Institute, University of Sydney ,","place":["Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2009,8,1]]},"reference":[{"key":"2025032709084902000_R1","first-page":"3537","article-title":"Evidence that cytokines play a role in rheumatoid arthritis.","volume-title":"J. Clin. Invest.","year":"2008"},{"key":"2025032709084902000_R2","first-page":"3557","article-title":"Nuanced roles of cytokines in three major human brain disorders.","volume-title":"J. Clin. Invest.","year":"2008"},{"key":"2025032709084902000_R3","first-page":"1635","article-title":"Delayed onset and reduced severity of collagen-induced arthritis in interleukin-6-deficient mice.","volume-title":"Arthritis Rheum.","year":"1999"},{"key":"2025032709084902000_R4","first-page":"41","article-title":"T cell self-reactivity forms a cytokine milieu for spontaneous development of IL-17+ Th cells that cause autoimmune arthritis.","volume-title":"J. Exp. Med.","year":"2007"},{"key":"2025032709084902000_R5","first-page":"1727","article-title":"Interleukin-6 functions in autoimmune encephalomyelitis: a study in gene-targeted mice.","volume-title":"Eur. J. Immunol.","year":"1998"},{"key":"2025032709084902000_R6","first-page":"6480","article-title":"IL-6-deficient mice are resistant to experimental autoimmune encephalomyelitis: roles of IL-6 in the activation and differentiation of autoreactive T cells.","volume-title":"J. Immunol.","year":"1998"},{"key":"2025032709084902000_R7","first-page":"235","article-title":"Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells.","volume-title":"Nature","year":"2006"},{"key":"2025032709084902000_R8","first-page":"6173","article-title":"Suppression of immune induction of collagen-induced arthritis in IL-17-deficient mice.","volume-title":"J. Immunol.","year":"2003"},{"key":"2025032709084902000_R9","first-page":"1133","article-title":"A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17.","volume-title":"Nat. Immunol.","year":"2005"},{"key":"2025032709084902000_R10","first-page":"231","article-title":"Transforming growth factor-\u03b2 induces development of the TH17 lineage.","volume-title":"Nature","year":"2006"},{"key":"2025032709084902000_R11","first-page":"1390","article-title":"TGF-\u03b2 and IL-6 drive the production of IL-17 and IL-10 by T cells and restrain TH-17 cell-mediated pathology.","volume-title":"Nat. Immunol.","year":"2007"},{"key":"2025032709084902000_R12","first-page":"179","article-title":"TGF\u03b2 in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells.","volume-title":"Immunity","year":"2006"},{"key":"2025032709084902000_R13","first-page":"2178","article-title":"IL-6-deficient mice resist myelin oligodendrocyte glycoprotein-induced autoimmune encephalomyelitis.","volume-title":"Eur. J. Immunol.","year":"1998"},{"key":"2025032709084902000_R14","first-page":"18460","article-title":"IL-6 controls Th17 immunity in vivo by inhibiting the conversion of conventional T cells into Foxp3+ regulatory T cells.","volume-title":"Proc. Natl. Acad. Sci. USA","year":"2008"},{"key":"2025032709084902000_R15","first-page":"357","article-title":"IL-6 in autoimmune disease and chronic inflammatory proliferative disease.","volume-title":"Cytokine Growth Factor Rev.","year":"2002"},{"key":"2025032709084902000_R16","first-page":"84","article-title":"Regulation of a lymphocyte-endothelial-IL-6 trans-signaling axis by fever-range thermal stress: hot spot of immune surveillance.","volume-title":"Cytokine","year":"2007"},{"key":"2025032709084902000_R17","first-page":"107","article-title":"Chronic complement C3 gene expression in the CNS of transgenic mice with astrocyte-targeted interleukin-6 expression.","volume-title":"Glia","year":"1996"},{"key":"2025032709084902000_R18","first-page":"766","article-title":"Evolution of neuropathologic abnormalities associated with blood-brain barrier breakdown in transgenic mice expressing interleukin-6 in astrocytes.","volume-title":"J. Neuropathol. Exp. Neurol.","year":"1995"},{"key":"2025032709084902000_R19","first-page":"10061","article-title":"Neurologic disease induced in transgenic mice by the cerebral overexpression of interleukin 6.","volume-title":"Proc. Natl. Acad. Sci. USA","year":"1993"},{"key":"2025032709084902000_R20","first-page":"212","article-title":"Reactive gliosis as a consequence of interleukin-6 expression in the brain: studies in transgenic mice.","volume-title":"Dev. Neurosci.","year":"1994"},{"key":"2025032709084902000_R21","first-page":"1500","article-title":"Progressive decline in avoidance learning paralleled by inflammatory neurodegeneration in transgenic mice expressing interleukin 6 in the brain.","volume-title":"Proc. Natl. Acad. Sci. USA","year":"1997"},{"key":"2025032709084902000_R22","first-page":"360","article-title":"Observer-rated ataxia: rating scales for assessment of genetic differences in ethanol-induced intoxication in mice.","volume-title":"J. Appl. Physiol.","year":"2004"},{"key":"2025032709084902000_R23","first-page":"7832","article-title":"Chemokine gene expression in the brain of mice with lymphocytic choriomeningitis.","volume-title":"J. Virol.","year":"1997"},{"key":"2025032709084902000_R24","first-page":"3602","article-title":"Patterns of cytokine gene expression by CD4+ T cells from young and old mice.","volume-title":"J. Immunol.","year":"1993"},{"key":"2025032709084902000_R25","first-page":"71","article-title":"Statistical analysis of data from studies on experimental autoimmune encephalomyelitis.","volume-title":"J. Neuroimmunol.","year":"2005"},{"key":"2025032709084902000_R26","first-page":"233","article-title":"Interleukin 6 production in the central nervous system during experimental autoimmune encephalomyelitis.","volume-title":"Eur. J. Immunol.","year":"1990"},{"key":"2025032709084902000_R27","first-page":"500","article-title":"Gene-microarray analysis of multiple sclerosis lesions yields new targets validated in autoimmune encephalomyelitis.","volume-title":"Nat. Med.","year":"2002"},{"key":"2025032709084902000_R28","first-page":"689","article-title":"On the cellular source and function of interleukin 6 produced in the central nervous system in viral disease.","volume-title":"Eur. J. Immunol.","year":"1989"},{"key":"2025032709084902000_R29","first-page":"521","article-title":"Targeting of adoptively transferred experimental allergic encephalitis lesion at sites of Wallerian degeneration.","volume-title":"Acta Neuropathol.","year":"1990"},{"key":"2025032709084902000_R30","first-page":"337","article-title":"Novel major histocompatibility complex expression by microglia and site-specific experimental allergic encephalomyelitis lesions in the rat central nervous system after optic nerve transection.","volume-title":"Adv. Neurol.","year":"1993"},{"key":"2025032709084902000_R31","first-page":"1563","article-title":"Targeting inflammatory demyelinating lesions to sites of wallerian degeneration.","volume-title":"Am. J. Pathol.","year":"2007"},{"key":"2025032709084902000_R32","first-page":"1031","article-title":"Role of chemokines, neuronal projections, and the blood-brain barrier in the enhancement of cerebral EAE following focal brain damage.","volume-title":"J. Neuropathol. Exp. Neurol.","year":"2000"},{"key":"2025032709084902000_R33","first-page":"343","article-title":"Strongly compromised inflammatory response to brain injury in interleukin-6-deficient mice.","volume-title":"Glia","year":"1999"},{"key":"2025032709084902000_R34","first-page":"4481","article-title":"Astrocyte-targeted expression of IL-12 induces active cellular immune responses in the central nervous system and modulates experimental allergic encephalomyelitis.","volume-title":"J. Immunol.","year":"2000"},{"key":"2025032709084902000_R35","first-page":"129","article-title":"Expression of ICAM-1, VCAM-1, L-selectin, and leukosialin in the mouse central nervous system during the induction and remission stages of experimental allergic encephalomyelitis.","volume-title":"J. Neuroimmunol.","year":"1994"},{"key":"2025032709084902000_R36","first-page":"15","article-title":"Expression of intercellular adhesion molecule-1 and lymphocyte function-associated antigen-1 in the spinal cord of rats during acute experimental allergic encephalomyelitis.","volume-title":"Autoimmunity","year":"1994"},{"key":"2025032709084902000_R37","first-page":"851","article-title":"Intercellular adhesion molecule-1 expression is required on multiple cell types for the development of experimental autoimmune encephalomyelitis.","volume-title":"J. Immunol.","year":"2007"},{"key":"2025032709084902000_R38","first-page":"429","article-title":"Increased expression of the \u03b24 and \u03b15 integrin subunits in cerebral blood vessels of transgenic mice chronically producing the pro-inflammatory cytokines IL-6 or IFN-\u03b1 in the central nervous system.","volume-title":"Mol. Cell. Neurosci.","year":"2006"},{"key":"2025032709084902000_R39","first-page":"97","article-title":"Migration of hematogenous cells through the blood brain barrier and the initiation of CNS inflammation.","volume-title":"Brain Pathol.","year":"1991"},{"key":"2025032709084902000_R40","first-page":"254","article-title":"T-lymphocyte entry into the central nervous system.","volume-title":"J. Neurosci. Res.","year":"1991"},{"key":"2025032709084902000_R41","first-page":"5656","article-title":"Loss of blood-brain barrier integrity in the spinal cord is common to experimental allergic encephalomyelitis in knockout mouse models.","volume-title":"Proc. Natl. Acad. Sci. USA","year":"2007"},{"key":"2025032709084902000_R42","first-page":"162","article-title":"Blood-brain barrier disruption and lesion localisation in experimental autoimmune encephalomyelitis with predominant cerebellar and brainstem involvement.","volume-title":"J. Neuroimmunol.","year":"2005"},{"key":"2025032709084902000_R43","first-page":"1181","article-title":"C10 is a novel chemokine expressed in experimental inflammatory demyelinating disorders that promotes the recruitment of macrophages to the central nervous system.","volume-title":"Am. J. Pathol.","year":"1999"},{"key":"2025032709084902000_R44","first-page":"1939","article-title":"Distinct expression and function of the novel mouse chemokine monocyte chemotactic protein-5 in lung allergic inflammation.","volume-title":"J. Exp. Med.","year":"1996"},{"key":"2025032709084902000_R45","first-page":"99","article-title":"Murine monocyte chemoattractant protein (MCP)-5: a novel CC chemokine that is a structural and functional homologue of human MCP-1.","volume-title":"J. Exp. Med.","year":"1997"},{"key":"2025032709084902000_R46","first-page":"713","article-title":"Absence of monocyte chemoattractant protein 1 in mice leads to decreased local macrophage recruitment and antigen-specific T helper cell type 1 immune response in experimental autoimmune encephalomyelitis.","volume-title":"J. Exp. Med.","year":"2001"},{"key":"2025032709084902000_R47","first-page":"1075","article-title":"Resistance to experimental autoimmune encephalomyelitis in mice lacking the CC chemokine receptor (CCR)2.","volume-title":"J. Exp. Med.","year":"2000"},{"key":"2025032709084902000_R48","first-page":"139","article-title":"Experimental autoimmune encephalomyelitis (EAE) in CCR2\u2212\/\u2212 mice: susceptibility in multiple strains.","volume-title":"Am. J. Pathol.","year":"2003"},{"key":"2025032709084902000_R49","first-page":"159","article-title":"Molecular properties of the chemokine receptor family.","volume-title":"Trends Pharmacol. Sci.","year":"1994"},{"key":"2025032709084902000_R50","first-page":"891","article-title":"Chemokines in innate and adaptive host defense: basic chemokinese grammar for immune cells.","volume-title":"Annu. Rev. Immunol.","year":"2004"}],"container-title":["The Journal of Immunology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/183\/3\/2079\/62694095\/9442.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/183\/3\/2079\/62694095\/9442.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,3,30]],"date-time":"2025-03-30T06:56:42Z","timestamp":1743317802000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jimmunol\/article\/183\/3\/2079\/8053766"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2009,8,1]]},"references-count":50,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2009,8,1]]}},"URL":"https:\/\/doi.org\/10.4049\/jimmunol.0900242","relation":{},"ISSN":["1550-6606","0022-1767"],"issn-type":[{"value":"1550-6606","type":"electronic"},{"value":"0022-1767","type":"print"}],"subject":[],"published-other":{"date-parts":[[2009,8]]},"published":{"date-parts":[[2009,8,1]]}}}