Regulation of signal transducer and activator of transcription and suppressor of cytokine-signaling gene expression in the brain of mice with astrocyte-targeted production of interleukin-12 or experimental autoimmune encephalomyelitis.
Interleukin (IL)-12 and interferon (IFN)-gamma are implicated in the pathogenesis of immune disorders of the central nervous system (CNS). To define the basis for the actions of these cytokines in the CNS, we examined the temporal and spatial regulation of key signal transducers and activators of transcription (STATs) and suppressors of cytokine signaling (SOCS) in the brain of transgenic mice with astrocyte production of IL-12 or in mice with experimental autoimmune encephalomyelitis (EAE). In healthy mice, with the exception of STAT4 and STAT6, the expression of a number of STAT and SOCS genes was detectable. However, in symptomatic transgenic mice and in EAE significant up-regulation of STAT1, STAT2, STAT3, STAT4, IRF9, and SOCS1 and SOCS3 RNA transcripts was observed. Although the increased expression of STAT1 RNA was widely distributed and included neurons, astrocytes, and microglia, STAT4 and STAT3 and SOCS1 and SOCS3 RNA was primarily restricted to the infiltrating mononuclear cell population. The level and location of the STAT1, STAT3, and STAT4 proteins overlapped with their corresponding RNA and additionally showed nuclear localization indicative of activation of these molecules. Thus, in both the glial fibrillary acidic protein-IL-12 mice and in EAE the CNS expression of key STAT and SOCS genes that regulate IL-12 (STAT4) and IFN-gamma (STAT1, SOCS1, and SOCS3) receptor signaling is highly regulated and compartmentalized. We conclude the interaction between these positive and negative signaling circuits and their distinct cellular locations likely play a defining role in coordinating the actions of IL-12 and IFN-gamma during the pathogenesis of type 1 immune responses in the CNS.
Maier
Joachim
J
Department of Neuropharmacology, The Scripps Research Institute, La Jolla, California 92037, USA.
Kincaid
Carrie
C
Pagenstecher
Axel
A
Campbell
Iain L
IL
D000818:Animals; D001253:Astrocytes / Q000378:metabolism*; D001921:Brain / Q000503:physiopathology*; D002490:Central Nervous System / Q000503:physiopathology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation; D018664:Interleukin-12 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic / Q000235:genetics; D009000:Monocytes / Q000502:physiology; D012333:RNA, Messenger / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics*; D014018:Tissue Distribution; D015534:Trans-Activators / Q000235:genetics* / Q000378:metabolism / Q000502:physiology
D012333:RNA, Messenger; D012097:Repressor Proteins; D015534:Trans-Activators; D018664:Interleukin-12