Interleukin-12 (IL-12), but not IL-23, induces the expression of IL-7 in microglia and macrophages: implications for multiple sclerosis.
Interleukin-12 (IL-12) p70 and IL-23 are bioactive cytokines and their biological functions are becoming clear. Increased expression of IL-7 in the central nervous system as well as in peripheral immune cells is associated with multiple sclerosis and experimental allergic encephalomyelitis. Here, we describe the induction of IL-7 in primary mouse and human microglia, BV-2 microglial cells, mouse peritoneal macrophages and astrocytes by IL-12p70. Interestingly, IL-12 strongly induced the expression of IL-7 whereas IL-23 and other p40 family members remained weak inducers of IL-7 in these cell types. Consistently, IL-12, but not IL-23 and other p40 family members, induced IL-7 promoter-driven luciferase activity in microglial cells. Among various stimuli tested, IL-12 emerged as the most potent stimulus followed by bacterial lipopolysaccharide and HIV-1 gp120 in inducing the activation of IL-7 promoter in microglial cells. Furthermore, increase in IL-7 mRNA expression by over-expression of IL-12p35 subunit, but not p40 and IL-23 p19 subunit, confirm that p35, but not p40 and p19, is responsible for the induction of IL-7. Finally, by using primary microglia from IL-12 receptor β1-deficient (IL-12Rβ1(-/-)) and IL-12Rβ2(-/-) mice, we demonstrate that IL-12 induces the expression of IL-7 in microglia and macrophages via both IL-12Rβ2 and IL-12Rβ1. These studies delineate a novel biological function of IL-12 that is absent in IL-23 and other p40 family members.
Department of Neurological Sciences, Rush University Medical Center, Chicago, IL, USA.
Malabendu
M
Jana
Susanta
S
Mondal
Arundhati
A
Jana
Kalipada
K
Pahan
D000818:Animals; D001253:Astrocytes / Q000276:immunology / Q000378:metabolism; D002478:Cells, Cultured; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D005260:Female; D017930:Genes, Reporter; D015699:HIV Envelope Protein gp120 / Q000276:immunology / Q000378:metabolism; D006801:Humans; D018664:Interleukin-12 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D053765:Interleukin-12 Subunit p35 / Q000276:immunology / Q000378:metabolism; D053762:Interleukin-12 Subunit p40 / Q000276:immunology / Q000378:metabolism; D053759:Interleukin-23 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D015851:Interleukin-7 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008156:Luciferases / Q000096:biosynthesis / Q000235:genetics; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017628:Microglia / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D009103:Multiple Sclerosis / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D061251:Primary Cell Culture; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000378:metabolism; D053707:Receptors, Interleukin-12 / Q000172:deficiency / Q000235:genetics; D011994:Recombinant Proteins / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction; D014162:Transfection; D015854:Up-Regulation
D015699:HIV Envelope Protein gp120; C508605:IL7 protein, human; C508859:Il12a protein, mouse; C508440:Il12rb1 protein, mouse; C508443:Il12rb2 protein, mouse; D053765:Interleukin-12 Subunit p35; D053762:Interleukin-12 Subunit p40; D053759:Interleukin-23; D015851:Interleukin-7; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D053707:Receptors, Interleukin-12; D011994:Recombinant Proteins; C514793:gp120 protein, Human immunodeficiency virus 1; D018664:Interleukin-12; D008156:Luciferases
interleukin-12; interleukin-12 receptor; interleukin-23; interleukin-7; microglia; neuroinflammation