Journal of Leukocyte Biology Myeloid cells, immune suppression, tumor immunology
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Originally published online as doi:10.1189/jlb.1207830 on June 13, 2008

Published online before print June 13, 2008
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(Journal of Leukocyte Biology. 2008;84:631-643.)
© 2008 by Society for Leukocyte Biology

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{dagger} and Paul T. Massa*,1

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

1 Correspondence: Department of Neurology, Upstate Medical University, State University of New York, 750 East Adams St., Syracuse, NY 13210, USA. 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-1β 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




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