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PMID: 22634618 Published · ppublish English Comparative Study Journal Article Research Support, N.I.H., Extramural

Transcriptional regulation of murine IL-33 by TLR and non-TLR agonists.

Journal of immunology (Baltimore, Md. : 1950) ·Vol. 189 ·No. 1 ·2012-07-01 ·Pages 50-60

Polumuri SK, Jayakar GG, Shirey KA, Roberts ZJ, Perkins DJ, Pitha PM, Vogel SN

Abstract

IL-33, a member of the IL-1 family of cytokines, is produced by many cell types, including macrophages, yet its regulation is largely unknown. Treatment of primary murine macrophages with a panel of TLR (e.g., TLR2, TLR3, TLR4, and TLR9) agonists and non-TLR (e.g., MDA5, RIG-I) agonists revealed a pattern of gene and protein expression consistent with a role for IFN regulatory factor-3 (IRF-3) in the expression of IL-33. Accordingly, induction of IL-33 mRNA was attenuated in IRF-3(-/-) macrophages and TBK-1(-/-) mouse embryonic fibroblasts. Despite the fact that all IL-33 agonists were IRF-3 dependent, LPS-induced IL-33 mRNA was fully inducible in IFN-β(-/-) macrophages, indicating that IL-33 is not dependent on IFN-β as an intermediate. Epinephrine and Bordetella pertussis adenylate cyclase toxin (ACT), cAMP-activating agents, activate CREB and greatly synergize with LPS to induce IL-33 mRNA in macrophages. Both LPS-induced and ACT/LPS-enhanced expression of IL-33 mRNA was partially, but significantly, inhibited by the protein kinase A inhibitor H-89 but not by tyrosine kinase or protein kinase C inhibitors. Two IL-33 mRNA species derived from two alternative promoters encode full-length IL-33; however, the shorter "A" species is preferentially induced by all IL-33-inducing agonists except Newcastle disease virus, a RIG-I agonist that induced expression of both "A" and "B" transcripts. Together, these studies greatly extend what is currently known about the regulation of IL-33 induction in macrophages stimulated by bacterial and viral agonists that engage distinct innate immune signaling pathways.

MeSH Terms
Animals Cells, Cultured Fibroblasts/immunology,microbiology,virology Immunity, Innate/genetics Interferon Regulatory Factor-3/deficiency,genetics Interleukin-33 Interleukins/biosynthesis,genetics Ligands Macrophages/immunology,microbiology,virology Mice Mice, Inbred C57BL Mice, Knockout Protein Serine-Threonine Kinases/deficiency,genetics RNA, Messenger/biosynthesis Signal Transduction/genetics,immunology Toll-Like Receptors/agonists,metabolism,physiology Transcriptional Activation/genetics,immunology
Chemicals
Il33 protein, mouse Interferon Regulatory Factor-3 Interleukin-33 Interleukins Irf3 protein, mouse Ligands RNA, Messenger Toll-Like Receptors Tbk1 protein, mouse Protein Serine-Threonine Kinases
Authors & Affiliations
7 authors, click to expand affiliations / ORCID
Polumuri Swamy Kumar
Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
Jayakar Gift Gunaraj
Shirey Kari Ann
Roberts Zachary J
Perkins Darren J
Pitha Paula M
Vogel Stefanie N
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Article Info
Journal
Journal of immunology (Baltimore, Md. : 1950)
Abbr.
J Immunol
ISSN
1550-6606
DOI
10.4049/jimmunol.1003554
Published
2012-07-01
Epub
2012-00-25
Pages
50-60
Language
English
Region
United States
NLM ID
2985117R
PMCID
PMC3437667
Subset
IM
Grants
NIAID NIH HHS · R01 AI018797 · United States
NIAID NIH HHS · R37 AI018797 · United States
NIAID NIH HHS · T32 AI007540 · United States
NIAID NIH HHS · AI189797 · United States
External Links
PubMed source DOI: 10.4049/jimmunol.1003554 PMC Full Text View journal details
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