Experimental autoimmune encephalitis and inflammation in the absence of interleukin-12.
IL-12 is considered a critical proinflammatory cytokine for autoimmune diseases such as multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis (EAE). IL-12 is a heterodimer composed of a p35 subunit and a common p40 subunit shared by other cytokines. Both IL-12 p40(-/-) and p35(-/-) mice fail to produce IL-12 p70 heterodimer. However, in contrast to p40(-/-) mice, p35(-/-) mice are highly susceptible to the induction of EAE, establishing that IL-12 p70 is not essential for the development of EAE. When compared with wild-type mice, both p40(-/-) and p35(-/-) mice show deficiencies in primary IFN-gamma responses by lymph node cells. Expression profiling of the inflamed CNS revealed that Th2 cytokines such as IL-4 and IL-10 are upregulated in p35(-/-) mice, whereas LT-alpha and TNF-alpha levels are reduced. These studies show that a molecule other than IL-12 p70, which uses the p40 subunit, fulfills the functions previously attributed to IL-12 with regard to the development and pathogenesis of this autoimmune disease.
Becher
Burkhard
B
Department of Microbiology and Immunology, Dartmouth Medical School, Lebanon, New Hampshire 03756, USA. burkhard.becher@dartmouth.edu
Durell
Brigit G
BG
Noelle
Randolph J
RJ
D000818:Animals; D016207:Cytokines / Q000096:biosynthesis; D004660:Encephalitis / Q000276:immunology / Q000473:pathology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology* / Q000473:pathology; D005260:Female; D007371:Interferon-gamma / Q000096:biosynthesis; D018664:Interleukin-12 / Q000235:genetics / Q000502:physiology*; D053765:Interleukin-12 Subunit p35; D053762:Interleukin-12 Subunit p40; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D021122:Protein Subunits; D013116:Spinal Cord / Q000276:immunology / Q000473:pathology; D018418:Th2 Cells / Q000276:immunology
D016207:Cytokines; D053765:Interleukin-12 Subunit p35; D053762:Interleukin-12 Subunit p40; D021122:Protein Subunits; D018664:Interleukin-12; D007371:Interferon-gamma