Induction of experimental autoimmune encephalomyelitis in IL-12 receptor-beta 2-deficient mice: IL-12 responsiveness is not required in the pathogenesis of inflammatory demyelination in the central nervous system.
IL-12 is thought to be involved in the susceptibility to experimental autoimmune encephalomyelitis (EAE), a Th1 cell-mediated autoimmune disorder of the CNS. IL-12 signals through a heterodimeric receptor (IL-12Rbeta1/IL-12Rbeta2), whose beta2-chain is up-regulated on activated, autoreactive Th1 cells. Contrary to the expectation that the absence of IL-12Rbeta2 would protect from EAE, we found that IL-12Rbeta2-deficient mice developed earlier and more severe disease, with extensive demyelination and CNS inflammation. The inflammatory cells were mainly comprised of CD4(+) T cells, monocyte/macrophages, and dendritic cells. Compared to wild-type mice, IL-12Rbeta2-deficient mice exhibited significantly increased autoantigen-induced proliferative response and increased production of TNF-alpha, GM-CSF, IL-17, IL-18/IL-18Ralpha, and NO. In addition, we found significantly increased levels of IL-23p19 mRNA expression in spleen cells from immunized IL-12Rbeta2(-/-) mice compared with wild-type mice. These findings indicate that IL-12 responsiveness is not required in the pathogenesis of inflammatory demyelination in the CNS, and that, in the absence of IL-12Rbeta2, increased IL-23 and other inflammatory molecules may be responsible for increased severity of EAE.
Zhang
Guang-Xian
GX
Department of Neurology, University of Pennsylvania School of Medicine, 3400 Spruce Street, Philadelphia, PA 19104, USA.
Gran
Bruno
B
Yu
Shuo
S
Li
Jifen
J
Siglienti
Ines
I
Chen
Xiaohan
X
Kamoun
Malek
M
Rostami
Abdolmohamad
A
D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000276:immunology; D016175:B-Lymphocyte Subsets / Q000276:immunology / Q000473:pathology; D015496:CD4-Positive T-Lymphocytes / Q000473:pathology; D020278:Demyelinating Autoimmune Diseases, CNS / Q000235:genetics / Q000276:immunology / Q000473:pathology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics* / Q000276:immunology* / Q000473:pathology; D018985:Epitopes, B-Lymphocyte / Q000276:immunology; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006023:Glycoproteins / Q000008:administration & dosage / Q000276:immunology; D007249:Inflammation / Q000235:genetics / Q000276:immunology; D018664:Interleukin-12 / Q000378:metabolism / Q000502:physiology*; D020382:Interleukin-18 / Q000096:biosynthesis / Q000378:metabolism; D053727:Interleukin-18 Receptor alpha Subunit; D053759:Interleukin-23; D053760:Interleukin-23 Subunit p19; D007378:Interleukins / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D063308:Myelin-Oligodendrocyte Glycoprotein; D010446:Peptide Fragments / Q000008:administration & dosage / Q000276:immunology; D012333:RNA, Messenger / Q000096:biosynthesis; D018123:Receptors, Interleukin / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics*; D053707:Receptors, Interleukin-12; D053724:Receptors, Interleukin-18; D012720:Severity of Illness Index; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000473:pathology; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology
D018985:Epitopes, B-Lymphocyte; D018984:Epitopes, T-Lymphocyte; D006023:Glycoproteins; C508443:Il12rb2 protein, mouse; C508573:Il18r1 protein, mouse; C508841:Il23a protein, mouse; D020382:Interleukin-18; D053727:Interleukin-18 Receptor alpha Subunit; D053759:Interleukin-23; D053760:Interleukin-23 Subunit p19; D007378:Interleukins; D063308:Myelin-Oligodendrocyte Glycoprotein; D010446:Peptide Fragments; D012333:RNA, Messenger; D018123:Receptors, Interleukin; D053707:Receptors, Interleukin-12; D053724:Receptors, Interleukin-18; C445081:myelin oligodendrocyte glycoprotein (35-55); D018664:Interleukin-12