Journal
JOURNAL OF IMMUNOLOGY
Volume 182, Issue 5, Pages 2948-2958Publisher
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.0801692
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Funding
- National Institutes of Health [HL-30923, HL-084917, AI057175, AI063031]
- National Research Service Award. University of North Carolina Center for AIDS Research
- Amgen/Federation of Clinical Immunology Societies Fellowship Award
- Southeast Regional Center of Excellence for Emerging Infections and Biodefense
- American Cancer Society
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NLR (nucleotide-binding domain, leucine-rich repeat) proteins are intracellular regulators of host defense and immunity. One NLR gene, NLRP12 (NLR family, pyrin domain containing 12)/Monarch-1, has emerged as an important inhibitor of inflammatory gene expression in human myeloid cells. This is supported by genetic analysis linking the loss of a functional NLRP12 protein to hereditary periodic fever. NLRP12 transcription is diminished by specific TLR stimulation and myeloid cell maturation, consistent with its role as a negative regulator of inflammation. The NLRP12 promoter contains a novel Blimp-1 (B lymphocyte-induced maturation protein-1)/PRDM1 (PR domain-containing 1, with ZNF domain) binding site, and Blimp-1 reduces NLRP12 promoter activity, expression, and histone 3 acetylation. Blimp-1 associates with the endogenous NLRP12 promoter in a TLR-inducible manner and mediates the down-regulation of NLRP12 expression by TLR agonists. As expected, the expression of NLRP12 and Blimp-1 is inversely correlated. Analysis of Blimp-l(-/-) murine myeloid cells provides physiologic evidence that Blimp-1 reduces NLRP12 gene expression during cell differentiation. This demonstrates a novel role for Blimp-1 in the regulation of an NLR gene. The Journal of Immunology, 2009, 182: 2948-2958.
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