title: Lipopolysaccharide decreases single immunoglobulin interleukin-1 receptor-related molecule (SIGIRR) expression by suppressing specificity protein 1 (Sp1) via the Toll-like receptor 4 (TLR4)-p38 pathway in monocytes and neutrophils.
abstract: Single immunoglobulin interleukin-1 receptor-related molecule (SIGIRR) is one of the immunoglobulin-like membrane proteins that is crucial for negative regulation of toll-like receptor 4 (TLR4) and interleukin-1 receptor. Despite the importance of understanding its expression and function, knowledge is limited on the regulatory mechanism in the epithelial tissues, such as the liver, lung, and gut, where its predominant expression is originally described. Here, we found expression of SIGIRR in non-epithelial innate immune cells, including primary peripheral blood monocytes, polymorphonuclear neutrophils, monocytic RAW264 cells, and neutrophilic-differentiated HL-60 cells. Consistent with previous findings in epithelial tissues, SIGIRR gene and protein expression were also down-regulated by LPS treatment in a time-dependent manner in primary blood monocytes and polymorphonuclear neutrophils. A reduction was also observed in RAW264 and differentiated HL-60 cells. Notably, exogenous introduction of the dominant negative form of TLR4 and siRNA of p38 resulted in inhibition of LPS-induced SIGIRR down-regulation, whereas treatment with p38 activator anisomycin showed a dose-dependent decrease in SIGIRR expression, suggesting TLR4-p38 signal as a critical pathway for LPS-induced SIGIRR down-regulation. Finally, reporter gene and chromatin immunoprecipitation assays demonstrated that Sp1 is a key factor that directly binds to the proximal promoter of SIGIRR gene and consequently regulates basal SIGIRR expression, which is negatively regulated by the LPS-dependent TLR4-p38 pathway. In summary, the data precisely demonstrate how LPS down-regulates SIGIRR expression and provide a role of LPS signal that counteracts Sp1-dependent basal promoter activation of SIGIRR gene via TLR4-p38 pathway in non-epithelial innate immune cells.
authors.affiliation: From the Department of Molecular Medicine, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto 862-0973, Japan, the Laboratory of Pharmacology, Division of Life Science, Faculty of Pharmaceutical Sciences, Sojo University, Kumamoto 860-0082, Japan.
authors.forename: Keiko
authors.initials: K
authors.lastname: Ueno-Shuto
authors.affiliation: the Department of Physiology and Lung Center, Temple University School of Medicine, Philadelphia, Pennsylvania 19140, and.
authors.forename: Kosuke
authors.initials: K
authors.lastname: Kato
authors.affiliation: From the Department of Molecular Medicine, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto 862-0973, Japan.
authors.forename: Yukihiro
authors.initials: Y
authors.lastname: Tasaki
authors.affiliation: From the Department of Molecular Medicine, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto 862-0973, Japan.
authors.forename: Miki
authors.initials: M
authors.lastname: Sato
authors.affiliation: the School of Pharmacy, Kyushu University of Health and Welfare, Nobeoka, Miyazaki 882-8508, Japan.
authors.forename: Keizo
authors.initials: K
authors.lastname: Sato
authors.affiliation: the Laboratory of Pharmacology, Division of Life Science, Faculty of Pharmaceutical Sciences, Sojo University, Kumamoto 860-0082, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Uchida
authors.affiliation: From the Department of Molecular Medicine, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto 862-0973, Japan.
authors.forename: Hiromichi
authors.initials: H
authors.lastname: Sakai
authors.affiliation: From the Department of Molecular Medicine, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto 862-0973, Japan.
authors.forename: Tomomi
authors.initials: T
authors.lastname: Ono
authors.affiliation: From the Department of Molecular Medicine, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto 862-0973, Japan.
authors.forename: Mary Ann
authors.initials: MA
authors.lastname: Suico
authors.affiliation: From the Department of Molecular Medicine, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto 862-0973, Japan.
authors.forename: Kazunori
authors.initials: K
authors.lastname: Mitsutake
authors.affiliation: the Laboratory of Pharmacology, Division of Life Science, Faculty of Pharmaceutical Sciences, Sojo University, Kumamoto 860-0082, Japan.
authors.forename: Naofumi
authors.initials: N
authors.lastname: Tokutomi
authors.affiliation: From the Department of Molecular Medicine, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto 862-0973, Japan.
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Kai
authors.affiliation: From the Department of Molecular Medicine, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto 862-0973, Japan, tshuto@gpo.kumamoto-u.ac.jp.
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Shuto
mesh_terms: D000818:Animals; D001483:Base Sequence; D015536:Down-Regulation; D006801:Humans; D008070:Lipopolysaccharides / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D051379:Mice; D008809:Mice, Inbred C3H; D008969:Molecular Sequence Data; D009000:Monocytes / Q000378:metabolism*; D009504:Neutrophils / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D017472:Receptors, Interleukin-1 / Q000235:genetics* / Q000378:metabolism*; D016329:Sp1 Transcription Factor / Q000235:genetics* / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism*
chemical_list: D008070:Lipopolysaccharides; D017472:Receptors, Interleukin-1; D016329:Sp1 Transcription Factor; D051197:Toll-Like Receptor 4; C546891:SIGIRR protein, human; C484529:SIGIRR protein, mouse
keywords: Gene Expression; Lipopolysaccharide (LPS); Monocyte; Neurotrophin; Promoter; Single Immunoglobulin IL-1R-related Molecule (SIGIRR); Specificity Protein 1 (Sp1); Toll-like Receptor (TLR); p38