title: IL-12p35-deficient mice are susceptible to experimental autoimmune encephalomyelitis: evidence for redundancy in the IL-12 system in the induction of central nervous system autoimmune demyelination.
abstract: Experimental autoimmune encephalomyelitis (EAE) serves as a model for multiple sclerosis and is considered a CD4(+), Th1 cell-mediated autoimmune disease. IL-12 is a heterodimeric cytokine, composed of a p40 and a p35 subunit, which is thought to play an important role in the development of Th1 cells and can exacerbate EAE. We induced EAE with myelin oligodendrocyte glycoprotein (MOG) peptide 35-55 (MOG(35-55)) in C57BL/6 mice and found that while IL-12p40-deficient (-/-) mice are resistant to EAE, IL-12p35(-/-) mice are susceptible. Typical spinal cord mononuclear cell infiltration and demyelination were observed in wild-type and IL-12p35(-/-) mice, whereas IL-12p40(-/-) mice had normal spinal cords. A Th1-type response to MOG(35-55) was observed in the draining lymph node and the spleen of wild-type mice. A weaker MOG(35-55)-specific Th1 response was observed in IL-12p35(-/-) mice, with lower production of IFN-gamma. By contrast, a Th2-type response to MOG(35-55) correlated with disease resistance in IL-12p40(-/-) mice. Production of TNF-alpha by microglia, CNS-infiltrating macrophages, and CD4(+) T cells was detected in wild-type and IL-12p35(-/-), but not in IL-12p40(-/-), mice. In addition, NO production was higher in IL-12p35(-/-) and wild-type mice than in IL-12p40(-/-) mice. These data demonstrate a redundancy of the IL-12 system in the induction of EAE and suggest that p40-related heterodimers, such as the recently cloned IL-23 (p40p19), may play an important role in disease pathogenesis.
authors.affiliation: Department of Neurology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
authors.forename: Bruno
authors.initials: B
authors.lastname: Gran
authors.forename: Guang-Xian
authors.initials: GX
authors.lastname: Zhang
authors.forename: Shuo
authors.initials: S
authors.lastname: Yu
authors.forename: Jifen
authors.initials: J
authors.lastname: Li
authors.forename: Xiao-Han
authors.initials: XH
authors.lastname: Chen
authors.forename: Elvira S
authors.initials: ES
authors.lastname: Ventura
authors.forename: Malek
authors.initials: M
authors.lastname: Kamoun
authors.forename: Abdolmohamad
authors.initials: A
authors.lastname: Rostami
mesh_terms: D000818:Animals; D016207:Cytokines / Q000096:biosynthesis; D020278:Demyelinating Autoimmune Diseases, CNS / Q000235:genetics* / Q000276:immunology* / Q000473:pathology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics* / Q000276:immunology* / Q000473:pathology; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006023:Glycoproteins / Q000008:administration & dosage; D007113:Immunity, Innate / Q000235:genetics; D016056:Immunodominant Epitopes / Q000008:administration & dosage; D007279:Injections, Subcutaneous; D018664:Interleukin-12 / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D053765:Interleukin-12 Subunit p35; D053762:Interleukin-12 Subunit p40; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D063308:Myelin-Oligodendrocyte Glycoprotein; D009569:Nitric Oxide / Q000096:biosynthesis; D010446:Peptide Fragments / Q000008:administration & dosage; D021122:Protein Subunits / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D013116:Spinal Cord / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: D016207:Cytokines; D006023:Glycoproteins; D016056:Immunodominant Epitopes; D053765:Interleukin-12 Subunit p35; D053762:Interleukin-12 Subunit p40; D063308:Myelin-Oligodendrocyte Glycoprotein; D010446:Peptide Fragments; D021122:Protein Subunits; D014409:Tumor Necrosis Factor-alpha; C445081:myelin oligodendrocyte glycoprotein (35-55); D018664:Interleukin-12; D009569:Nitric Oxide