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Existence of seven human IL-1R1 promoters.

ABSTRACT: Previous studies have reported the existence of three promoters for the human type I interleukin-1 receptor (hIL-1R1) gene. These promoters were discovered by identifying discrete transcription start sites (TSS) from limited human cell lines. In this study, we examined the TSSs of hIL-1R1 mRNA from 24 different tissues and identified several novel TSSs in hIL-1R1 that suggest the existence of seven hIL-1R1 promoters: three of them are the same as those reported previously and four are putative novel promoters. Using a promoter-reporter assay, we show here that these promoters can drive the transcription of the reporter gene. In addition, these promoters exhibit cell type specific expression patterns and they can be regulated by enhancer elements in a cell type specific manner. Only one of the promoters was found to be sensitive to the stimulation by glucocorticoids. Similar to our recent report on murine IL-1R1, two of the hIL-1R1 promoters appear to be the dominant promoters, one of which was published previously and the other is identified in the present study. We also found an internal promoter that drives the expression of IL-1R1 after the conventional translation start codon, suggesting that a truncated hIL-1R1 may be expressed by this promoter. These results provide additional information regarding the transcription of hIL-1R1.

SUBMITTER: Li Q

PROVIDER: S-EPMC2931344 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Interleukin-1β (IL-1β) is one of the most potent pro-inflammatory cytokines implicated in a wide range of autoinflammatory, autoimmune, infectious, and degenerative diseases. Therefore, many researchers have focused on developing therapeutic molecules that inhibit IL-1β-IL-1 receptor 1 (IL-1R1) interaction for the treatment of IL-1-related diseases. Among IL-1-related diseases, osteoarthritis (OA), is characterized by progressive cartilage destruction, chondrocyte inflammation, and extracellular matrix (ECM) degradation. Tannic acid (TA) has been proposed to have multiple beneficial effects, including anti-inflammatory, anti-oxidant, and anti-tumor activities. However, it is unclear whether TA plays a role in anti-IL-1β activity by blocking IL-1β-IL-1R1 interaction in OA. In this study, we report the anti-IL-1β activity of TA in the progression of OA in both in vitro human OA chondrocytes and in vivo rat OA models. Herein, using-ELISA-based screening, natural compound candidates capable of inhibiting the IL-1β-IL-1R1 interaction were identified. Among selected candidates, TA showed hindering IL-1β-IL-1R1 interaction by direct binding to IL-1β using surface plasmon resonance (SPR) assay. In addition, TA inhibited IL-1β bioactivity in HEK-Blue IL-1-dependent reporter cell line. TA also inhibited IL-1β-induced expression of inducible nitric oxide synthase (NOS2), cyclooxygenase-2 (COX-2), IL-6, tumor necrosis factor-alpha (TNF-α), nitric oxide (NO), and prostaglandin E2 (PGE2) in human OA chondrocytes. Moreover, TA downregulated IL-1β-stimulated matrix metalloproteinase (MMP)3, MMP13, ADAM metallopeptidase with thrombospondin type 1 motif (ADAMTS)4, and ADAMTS5, while upregulating collagen type II (COL2A1) and aggrecan (ACAN). Mechanistically, we confirmed that TA suppressed IL-1β-induced MAPK and NF-κB activation. The protective effects of TA were also observed in a monosodium iodoacetamide (MIA)-induced rat OA model by reducing pain and cartilage degradation and inhibiting IL-1β-mediated inflammation. Collectively, our results provide evidence that TA plays a potential role in OA and IL-1β-related diseases by hindering IL-1β-IL-1R1 interaction and suppressing IL-1β bioactivity.

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Existence of seven human IL-1R1 promoters.

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