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

• Published in: The Journal of biological chemistry Vol. 289; no. 26; pp. 18097 - 18109
• Main Authors: Ueno-Shuto, Keiko, Kato, Kosuke, Tasaki, Yukihiro, Sato, Miki, Sato, Keizo, Uchida, Yuji, Sakai, Hiromichi, Ono, Tomomi, Suico, Mary Ann, Mitsutake, Kazunori, Tokutomi, Naofumi, Kai, Hirofumi, Shuto, Tsuyoshi
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 27-06-2014; American Society for Biochemistry and Molecular Biology
• Subjects: Animals; Base Sequence; Down-Regulation; Gene Expression; Gene Regulation; Humans; Lipopolysaccharide (LPS); Lipopolysaccharides - metabolism; MAP Kinase Signaling System; Mice; Mice, Inbred C3H; Molecular Sequence Data; Monocyte; Monocytes - metabolism; Neurotrophin; Neutrophils - metabolism; p38; Promoter; Promoter Regions, Genetic; Receptors, Interleukin-1 - genetics; Receptors, Interleukin-1 - metabolism; Single Immunoglobulin IL-1R-related Molecule (SIGIRR); Sp1 Transcription Factor - genetics; Sp1 Transcription Factor - metabolism; Specificity Protein 1 (Sp1); Toll-like Receptor (TLR); Toll-Like Receptor 4 - genetics; Toll-Like Receptor 4 - metabolism; Neurotrophin; Promoter; Specificity Protein 1 (Sp1); Gene Expression; Monocyte; p38; Single Immunoglobulin IL-1R-related Molecule (SIGIRR); Toll-like Receptor (TLR); Lipopolysaccharide (LPS)
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M113.532093

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.
Background: Single immunoglobulin interleukin-1 receptor-related molecule (SIGIRR) is a negative inflammatory regulator whose regulatory mechanism is mainly described in epithelial tissues.
Results: Higher monocytic and neutrophilic SIGIRR expression is maintained by Sp1.
Conclusion: Lipopolysaccharide decreases SIGIRR expression by suppressing Sp1 via the TLR4-p38 pathway.
Significance: The LPS-dependent SIGIRR down-regulation may be critical for optimal inflammatory responses in immune cells.