IL‐1β‐mediated up‐regulation of DEC1 in human gingiva cells via the Akt pathway

Abstract

Growing evidence indicates that inflammation is a contributing factor leading to cancer development. However, pathways involved in this progression are not well understood. The involvement of DEC1 in cancer prompted us to examine whether pro-inflammatory cytokine interleukin-1β (IL-1β) induces the expression of DEC1 in oral inflammation. We found that IL-1β up-regulated DEC1 and hypoxia-inducible factor-1α (HIF-1α) protein and elevated the HIF-1α-responsive gene vascular endothelial growth factor (VEGF) expression in human primary gingival cells. HIF-1α and DEC1 immunoreactivity were significantly higher in the cases of gingival inflammation. We demonstrate that IL-1β up-regulates DEC1 and HIF-1α protein through a classical inflammatory signaling pathway involving Akt. Our data strongly suggest that PI-3K-Akt is an upstream participant in IL-1β-mediated DEC1 and HIF-1α induction. This is supported by the following data: (1) IL-1β induces 473 serine phosphorylation of Akt; (2) IL-1β-mediated Akt activation occurs in a PI-3K-dependent manner, and specific inhibition of PI-3K prevents Akt phosphorylation; and (3) inhibition of Akt prevents IL-1β-mediated DEC1 and HIF-1α induction. Taken together, these results suggest that DEC1 is one of the important transcription factors in inflammation.

Circadian gene variants in cancer

“…In humans, SNPs, deletion and/or deregulation of Dec1 or 2 are associated with gastric, non-small-cell lung, pancreatic, endometrial, renal, and breast cancers, HCC, head and neck esophageal squamous cell carcinoma and lymph node metastasis (182–191), sleep disorders (192), and inflammation and autoimmune disease (193, 194). Mice lacking Dec1 or 2 ( Dec1 −/− or Dec2 −/− ) maintain normal circadian rhythmicity.…”

DEC1/STRA13/SHARP2 and DEC2/SHARP1 Coordinate Physiological Processes, Including Circadian Rhythms in Response to Environmental Stimuli

“…Up -Fibroblasts (Ueshima et al, 2012) Dec1 Down Down Fibroblasts Li et al, 2003) Dec2 Down Down Fibroblasts, 10T1/2 cells (Azmi, Sun, Ozog, & Taneja, 2003;Hamaguchi et al, 2004) PER1, PER2 Down Down Fibroblasts (Hamaguchi et al, 2004;Kawamoto et al, 2004) CRY1, CRY2 Down Down Fibroblasts (Grechez-Cassiau et al, 2004;Hamaguchi et al, 2004) (Ehata et al, 2007;Kon et al, 2008) Cyclic AMP Up -Chondrocytes, podocytes (Bek et al, 2003;Shen et al, 1997Shen et al, , 2001 ALK Up -Fibroblasts (Kon et al, 2008) PI3 kinase Up -Liver, gingiva (Yamada et al, 2003;Bhawal et al, 2012) Akt Up -Gingiva MAPK p38 -Up Bone marrow (Bragado et al, 2013) d. Growth factors, hormones, and autacoids TGF-β Up Up Keratinocytes, chondrocytes, kidney, tumors (Bragado et al, 2013;Kon et al, 2008;Sato et al, 2012;Shen et al, 2002;Zawel et al, 2002) BMP-2 Up -Chondrocytes (Shen et al, 2002) Activin Retinoic acid Up -P19 cells, podocytes (Bek et al, 2003;Boudjelal et al, 1997) Vitamin D Up -Leukemia (Seuter et al, 2013) Continued Up -Natural killer cells, gingiva Ivanova et al, 2004) IL-4, LPS Down -B cells (Seimiya et al, 2002) TNF-α, IFN-β Up -Natural killer cells, fibroblasts (Ivanova et al, 2004;Petrzilka, Taraborrelli, Cavadini, Fontana, & Birchler, 2009) SCF Up -Hematopoietic cells (Pedersen et al, 2008) f. Nutrients…”

“…IL-1β enhances Dec1 expression in gingival epithelial cells, but not gingival fibroblasts, via the PI3 kinase and Akt/protein kinase B pathway (Table 10.2c; Bhawal et al, 2012). On the other hand, various stimuli that activate B lymphocytes, including IL-4, lipopolysaccharide (LPS), CD40 ligand, and anti-IgM antibodies, downregulate Dec1 (Seimiya et al, 2002).…”

Decreased carboxylesterases expression and hydrolytic activity in type 2 diabetic mice through Akt/mTOR/HIF-1α/Stra13 pathway

“…Other studies reported insulin could increase the expression of mTOR and HIF-1a in HepG2 and HL7702 cells (Li et al, 2013). IL-1b up-regulated HIF-1a and DEC1 in human primary gingival cells via the Akt pathway (Bhawal et al, 2012). The DEC1 expression was highly elevated in response to internal and external environmental stimuli such as hypoxia, insulin, and cytokines (Ivanova et al, 2004;Miyazaki et al, 2002;Yamada et al, 2003).…”