Interleukin-12 (IL-12), but not IL-23, induces the expression of IL-7 in microglia and macrophages: implications for multiple sclerosis

Immunology. 2014 Apr;141(4):549-63. doi: 10.1111/imm.12214.

Abstract

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.

Keywords: interleukin-12; interleukin-12 receptor; interleukin-23; interleukin-7; microglia; neuroinflammation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Astrocytes / immunology
  • Astrocytes / metabolism
  • Cells, Cultured
  • Encephalomyelitis, Autoimmune, Experimental / genetics
  • Encephalomyelitis, Autoimmune, Experimental / immunology
  • Encephalomyelitis, Autoimmune, Experimental / metabolism*
  • Female
  • Genes, Reporter
  • HIV Envelope Protein gp120 / immunology
  • HIV Envelope Protein gp120 / metabolism
  • Humans
  • Interleukin-12 / genetics
  • Interleukin-12 / immunology
  • Interleukin-12 / metabolism*
  • Interleukin-12 Subunit p35 / immunology
  • Interleukin-12 Subunit p35 / metabolism
  • Interleukin-12 Subunit p40 / immunology
  • Interleukin-12 Subunit p40 / metabolism
  • Interleukin-23 / genetics
  • Interleukin-23 / immunology
  • Interleukin-23 / metabolism*
  • Interleukin-7 / genetics
  • Interleukin-7 / immunology
  • Interleukin-7 / metabolism*
  • Lipopolysaccharides / pharmacology
  • Luciferases / biosynthesis
  • Luciferases / genetics
  • Macrophages, Peritoneal / drug effects
  • Macrophages, Peritoneal / immunology
  • Macrophages, Peritoneal / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Microglia / drug effects
  • Microglia / immunology
  • Microglia / metabolism*
  • Multiple Sclerosis / genetics
  • Multiple Sclerosis / immunology
  • Multiple Sclerosis / metabolism*
  • Primary Cell Culture
  • Promoter Regions, Genetic
  • RNA, Messenger / metabolism
  • Receptors, Interleukin-12 / deficiency
  • Receptors, Interleukin-12 / genetics
  • Recombinant Proteins / immunology
  • Recombinant Proteins / metabolism
  • Signal Transduction
  • Transfection
  • Up-Regulation

Substances

  • HIV Envelope Protein gp120
  • IL7 protein, human
  • Il12a protein, mouse
  • Il12rb1 protein, mouse
  • Il12rb2 protein, mouse
  • Interleukin-12 Subunit p35
  • Interleukin-12 Subunit p40
  • Interleukin-23
  • Interleukin-7
  • Lipopolysaccharides
  • RNA, Messenger
  • Receptors, Interleukin-12
  • Recombinant Proteins
  • gp120 protein, Human immunodeficiency virus 1
  • Interleukin-12
  • Luciferases