Induction of IL-33 expression and activity in central nervous system glia.
IL-33 is a novel member of the IL-1 cytokine family and a potent inducer of type 2 immunity, as mast cells and Th2 CD4+ T cells respond to IL-33 with the induction of type 2 cytokines such as IL-13. IL-33 mRNA levels are extremely high in the CNS, and CNS glia possess both subunits of the IL-33R, yet whether IL-33 is produced by and affects CNS glia has not been studied. Here, we demonstrate that pathogen-associated molecular patterns (PAMPs) significantly increase IL-33 mRNA and protein expression in CNS glia. Interestingly, IL-33 was localized to the nucleus of astrocytes. Further, CNS glial and astrocyte-enriched cultures treated with a PAMP followed by an ATP pulse had significantly higher levels of supernatant IL-1beta and IL-33 than cultures receiving any single treatment (PAMP or ATP). Supernatants from PAMP + ATP-treated glia induced the secretion of IL-6, IL-13, and MCP-1 from the MC/9 mast cell line in a manner similar to exogenous recombinant IL-33. Further, IL-33 levels and activity were increased in the brains of mice infected with the neurotropic virus Theiler's murine encephalomyelitis virus. IL-33 also had direct effects on CNS glia, as IL-33 induced various innate immune effectors in CNS glia, and this induction was greatly amplified by IL-33-stimulated mast cells. In conclusion, these results implicate IL-33-producing astrocytes as a potentially critical regulator of innate immune responses in the CNS.
Department of Neurology and Interest Group in Neuro-Immune Interactions, SUNY Upstate Medical University, Syracuse, New York 13210, USA.
Chad A
CA
Hudson
George P
GP
Christophi
Ross C
RC
Gruber
Joel R
JR
Wilmore
David A
DA
Lawrence
Paul T
PT
Massa
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000276:immunology / Q000378:metabolism* / Q000821:virology; D018188:Cardiovirus Infections / Q000378:metabolism* / Q000821:virology; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D007124:Immunoenzyme Techniques; D053583:Interleukin-1beta; D000067596:Interleukin-33; D007378:Interleukins / Q000235:genetics* / Q000378:metabolism; D008407:Mast Cells / Q000378:metabolism / Q000821:virology; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D009457:Neuroglia / Q000378:metabolism* / Q000821:virology; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017945:Theilovirus / Q000235:genetics / Q000378:metabolism
D016207:Cytokines; C506535:Il33 protein, mouse; D053583:Interleukin-1beta; D000067596:Interleukin-33; D007378:Interleukins; D012333:RNA, Messenger; D000255:Adenosine Triphosphate