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Departments of
* Cell Biology and
Immunology, Duke University Medical Center, Durham NC 27710;
Lineberger Comprehensive Cancer Center, the University of North Carolina at Chapel Hill, Chapel Hill, NC 27599; and
Departments of Microbiology and Biochemistry & Molecular Biophysics, Columbia University College of Physicians and Surgeons, New York, NY 10032
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-1–/– 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 costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by National Institutes of Health Grants HL-30923 and HL-084917 (to J.R.W.) and AI057175 and AI063031 (to J.P.T.), as well as a 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, and support from the American Cancer Society (to K.L.W.).
2 Current address: Department of Dermatology, Asahikawa Medical College, Asahikawa, Japan.
3 Address correspondence and reprint requests to Dr. Kristi L. Williams, Department of Cell Biology, Box 3709, Duke University Medical Center, Durham, NC 27710. E-mail address: klw{at}cellbio.duke.edu
4 Abbreviations used in this paper: NLR, nucleotide-binding domain, leucine-rich repeat; HPF, hereditary periodic fever; NLRP12, NLR family, pyrin domain containing 12; IRAK, IL-1R-associated kinase; NIK, NF-
B-inducing kinase; Blimp-1, B lymphocyte-induced maturation protein-1; PRDM1, PR domain-containing 1, with ZNF domain; HKLM, heat-killed Listeria monocytogenes; qPCR, quantitative PCR; DAPA, DNA affinity purification assay; ChIP, chromatin immunoprecipitation; DRB, 5,6-dichlororibofuranosyl benzimidazole; GusB, β-glucuronidase.
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