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Published online before print June 13, 2008

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© by The Society for Leukocyte Biology
Journal of Leukocyte Biology, doi:10.1189/jlb.1207830

Received for publication December 14, 2007.
Revised May 12, 2008.
Accepted for publication May 19, 2008.

Article

Induction of IL-33 expression and activity in central nervous system glia

Chad A. Hudson ^*, George P. Christophi ^*, Ross C. Gruber ^*, Joel R. Wilmore ^*, David A. Lawrence , and Paul T. Massa ^*@

*Department of Neurology and Interest Group in Neuro-Immune Interactions, SUNY Upstate Medical University, Syracuse, New York, USA; and Clinical and Experimental Endocrinology and Immunology, Wadsworth Center, Albany, New York, USA

^@ To whom correspondence should be addressed. E-mail: massap{at}upstate.edu.

	Abstract

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-1 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.

Key Words: IL-1 family cytokines • IL-13 • astrocyte • pathogen-associated molecular pattern