Abstract
S100A9 is a calcium-binding protein and subunit of antimicrobial calprotectin complex (S100A8/A9). Produced by neutrophils, monocytes/macrophages and keratinocytes, S100A9 expression increases in response to inflammation. For example, IL-1α produced by epithelial cells acts autonomously on the same cells to induce the expression of S100A8/A9 and cellular differentiation. Whereas it is well known that IL-1α and members of the IL-10 family of cytokines upregulate S100A8 and S100A9 in several cell lineages, the pathway and mechanism of IL-1α-dependent transcriptional control of S100A9 in epithelial cells are not established. Modeled using human epidermal keratinocytes (HaCaT cells), IL-1α stimulated the phosphorylation of p38 MAPK and induced S100A9 expression, which was blocked by IL-1 receptor antagonist, RNAi suppression of p38, or a p38 MAPK inhibitor. Transcription of S100A9 in HaCaT cells depended on nucleotides -. 94 to -. 53 in the upstream promoter region, based upon the use of deletion constructs and luciferase reporter activity. Within the responsive promoter region, IL-1α increased the binding activity of CCAAT/enhancer binding protein β (C/EBPβ). Mutated C/EBPβ binding sequences or C/EBPβ-specific siRNA inhibited the S100A9 transcriptional response. Hence, IL-1α is strongly suggested to increase S100A9 expression in a human epidermal keratinocyte cell line by signaling through the IL-1 receptor and p38 MAPK, increasing C/EBPβ-dependent transcriptional activity.
Original language | English (US) |
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Pages (from-to) | 954-962 |
Number of pages | 9 |
Journal | Biochimica et Biophysica Acta - Gene Regulatory Mechanisms |
Volume | 1829 |
Issue number | 9 |
DOIs | |
State | Published - Sep 2013 |
Bibliographical note
Funding Information:We thank Ali Khammanivong for informatics support. This study was supported in part by grants-in aid ( 19592388 , 21592625 and 24593125 ) for the Scientific Research from the Japan Society for the Promotion of Science and NIH grants R01DE11831 and R01DE021206 to MCH. Appendix A
Keywords
- C/EBPβ
- IL-1α
- Keratinocytes
- P38
- S100A9