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.
Highlights
Single immunoglobulin interleukin-1 receptor-related molecule (SIGIRR) is a negative inflammatory regulator whose regulatory mechanism is mainly described in epithelial tissues
Pretreatment with the antibody against SIGIRR ectodomain, which is considered to interfere with its dimerization that is crucial for its inhibitory function of LPS-toll-like receptor 4 (TLR4) signal, resulted in the dramatic enhancement of LPS-induced IL-8 production compared with control IgG-pretreated cells (Fig. 1C)
Our findings on the prevalence of functional expression of SIGIRR and its downregulation by LPS in monocytic and neutrophilic cells alongside these studies showing a contributory role of non-epithelial systems under physiological and pathophysiological conditions further highlighted the need for a better understanding of how SIGIRR expression is regulated in this lesser-studied non-epithelial innate immune systems
Summary
Single immunoglobulin interleukin-1 receptor-related molecule (SIGIRR) is a negative inflammatory regulator whose regulatory mechanism is mainly described in epithelial tissues. 5Ј-TTCAGTCCAGTGGCTGAAAGACGG-3Ј 5Ј-ACCTCTGACAGGTTGGCCTTGAC-3Ј 5Ј-CTGGCCGTGGCTCTCTTG-3Ј 5Ј-CCTTGGCAAAACTGCACCTT-3Ј 5Ј-CGGCTACCACATCCAAGGAA-3Ј 5Ј-GCTGGAATTACCGCGGCT-3Ј 5Ј-GTGGCTGAAAGATGGTCTGGCATTG-3Ј 5Ј-CAGGTGAAGGTTCCATAGTCCTCTGC-3Ј 5Ј-CATCTTCTCAAAATTCGAGTGACAA-3Ј 5Ј-TGGGAGTAGACAAGGTACAACCC-3Ј 5Ј-CCATCCAATCGGTAGTAGCG-3Ј 5Ј-GTAACCCGTTGAACCCCATT-3Ј 5Ј-CCCAAAGGCGCACCAATGACC-3Ј 5Ј-GTGGCGGTCGCCATCAGACC-3Ј 5Ј-CGCACCTGGCTCAGGTGAGC-3Ј 5Ј-CTCGGCCAGCAGACTGATCCA-3Ј naling, including T1/ST2 [5], single immunoglobulin IL-1Rrelated molecule (SIGIRR) [6], splicing variant of myeloid differentiation factor 88 (MyD88s) [7], suppressor of cytokine signaling 1 (SOCS1) [8], and Triad3A [9], are crucial for appropriate immune responses because the mice lacking these negative regulators typically exhibit enhanced inflammatory responses leading to tissue damage These suggest the importance of understanding the expression and function of the negative regulators of TIR signaling. Our study further uncovers a role of LPS signal that counteracts Sp1-dependent basal promoter activation of SIGIRR gene via TLR4-p38 pathway
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