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The synergistic effects of IL-6/IL-17A promote osteogenic differentiation by improving OPG/RANKL ratio and adhesion of MC3T3-E1 cells on hydroxyapatite

Sritharan S, Kannan TP, Norazmi MN, Nurul AA

J Craniomaxillofac Surg, 2018 Aug;46(8):1361-1367.
PMID: 29805067 DOI: 10.1016/j.jcms.2018.05.002

OBJECTIVE: In this study, we evaluated the potential role of IL-6 and/or IL-17A in regulating the OPG/RANKL (osteoprotegerin/receptor activator of nuclear factor kappa b ligand) system of murine osteoblast cell line (MC3T3-E1) cultured on hydroxyapatite (HA).
METHODS: MC3T3-E1 cells were seeded on HA and treated with recombinant IL-6 or rIL-17A or combination of the two cytokines. Cell proliferation and differentiation activity were measured by MTS and alkaline phosphatase assays respectively. Observation of cell adhesion and proliferation was examined by scanning electron microscopy. Gene and protein expressions were performed on RANKL and OPG using qPCR, Western blot and ELISA.
RESULTS: We demonstrated that treatment with recombinant IL-17A (rIL-17A) and the combination rIL-6/rIL-17A promoted better adhesion and higher proliferation of cells on HA. Cells treated with rIL-17A and the combination cytokines showed a significant increase in differentiation activity on day 7, 10 and 14 as indicated by ALP activity (p 6/IL-17A) has synergistic effects to promote osteoblastic differentiation but suppress osteoclastogenesis by altering the OPG/RANKL ratio.

Matched MeSH terms: Interleukin-6/pharmacology*
Interleukin-6 inhibits human peroxisome proliferator activated receptor alpha gene expression via CCAAT/enhancer-binding proteins in hepatocytes

Chew CH, Chew GS, Najimudin N, Tengku-Muhammad TS

Int J Biochem Cell Biol, 2007;39(10):1975-86.
PMID: 17616429

Peroxisome proliferator activated receptor alpha has been implicated as a regulator of acute phase response genes in hepatocytes. Interleukin-6 is widely known as a major cytokine responsible in the regulation of acute phase proteins and, therefore, acute phase response. Unfortunately, to date, very little is understood about the molecular mechanisms by which interleukin-6 regulates the gene expression of peroxisome proliferator activated receptor alpha. Here, we report the molecular mechanisms by which peroxisome proliferator activated receptor alpha was regulated by interleukin-6 in human HepG2 cells. Interleukin-6 was shown to down-regulate the peroxisome proliferator activated receptor alpha gene expression at the level of gene transcription. Functional dissection of human peroxisome proliferator activated receptor alpha promoter B revealed the role of predicted CCAAT/enhancer-binding protein binding site (-164/+34) in mediating the interleukin-6 inhibitory effects on peroxisome proliferator activated receptor alpha mRNA expression and electrophoretic mobility shift assay showed the binding of CCAAT/enhancer-binding protein isoforms to this cis-acting elements was increased in interleukin-6-treated HepG2 cells. Co-transfection experiments, then, demonstrated that CCAAT/enhancer-binding protein beta either in homodimer or heterodimer with CCAAT/enhancer-binding protein alpha and CCAAT/enhancer-binding protein delta plays a predominant role in inhibiting the transcriptional activity of peroxisome proliferator activated receptor alpha promoter B, thus, reducing the peroxisome proliferator activated receptor alpha mRNA expression. These studies, therefore, suggest a novel mechanism for interleukin-6-mediated inhibition of peroxisome proliferator activated receptor alpha gene expression that involves the activation of CCAAT/enhancer-binding protein isoforms with CCAAT/enhancer-binding protein beta may play a major role.

Matched MeSH terms: Interleukin-6/pharmacology*
Cord blood CD34+ cells cultured with FLT3L, stem cell factor, interleukin-6, and IL-3 produce CD11c+CD1a-/c- myeloid dendritic cells

Fadilah SA, Vuckovic S, Khalil D, Hart DN

Stem Cells Dev, 2007 Oct;16(5):849-55.
PMID: 17999605

Methods that allow expansion of myeloid dendritic cells (MDCs) from CD34(+) cells are potentially important for boosting anti-leukemic responses after cord blood (CB) hematopoietic stem cell transplantation (HSCT). We showed that the combination of early-acting cytokines FLT3-ligand (FL), stem cell factor (SCF), interleukin (IL)-3, and IL-6 supported the generation of CD11c(+)CD16() CD1a()/c() MDCs from CB CD34(+) cells or CB myeloid precursors. Early-acting cytokine-derived MDCs were maintained within the myeloid CD33(+)CD14()CD15() precursors with a mean of 4 x 10(6) cells generated from 1-4 x 10(4) CB CD34(+) cells or myeloid precursors after 2 weeks. After 8-12 days of culture the MDCs expressed higher levels of HLA-DR antigen but lower levels of CD40 and CD86 antigen, compared to adult blood MDCs. At this stage of differentiation, the early-acting cytokine-derived MDCs had acquired the ability to induce greater allogeneic T cell proliferation than monocytes or granulocytes derived from same culture. Early-acting cytokine-derived MDCs exposed to the cytokine cocktail (CC) comprising IL-1beta, IL-6, tumor necrosis factor (TNF)-alpha, and prostaglandin E (PGE)-2, upregulated the surface co-stimulatory molecules CD40 and CD86 and enhanced allogeneic T cell proliferation, as is characteristic of MDCs maturation. The reliable production of MDCs from CB CD34(+) cells provides a novel way to study their lineage commitment pathway(s) and also a potential means of enriching CB with MDCs to improve prospects for DC immunotherapy following CB HSCT.

Matched MeSH terms: Interleukin-6/pharmacology
Effects of IL-6, IL-10 and TGF-β on the expression of survivin and apoptosis in nasopharyngeal carcinoma TW01 cells

Poh YW, Gan SY, Tan EL

Exp Oncol, 2012 Jul;34(2):85-9.
PMID: 23013758

The aim of this study is to investigate whether IL-6, IL-10 and TGF-β are able to confer resistance to apoptosis in nasopharyngeal carcinoma cells by upregulating the expression of survivin.

Matched MeSH terms: Interleukin-6/pharmacology*
Interleukin-6 inhibition of peroxisome proliferator-activated receptor alpha expression is mediated by JAK2- and PI3K-induced STAT1/3 in HepG2 hepatocyte cells

Chew GS, Myers S, Shu-Chien AC, Muhammad TS

Mol Cell Biochem, 2014 Mar;388(1-2):25-37.
PMID: 24242046 DOI: 10.1007/s11010-013-1896-z

Interleukin-6 (IL-6) is the major activator of the acute phase response (APR). One important regulator of IL-6-activated APR is peroxisome proliferator-activated receptor alpha (PPARα). Currently, there is a growing interest in determining the role of PPARα in regulating APR; however, studies on the molecular mechanisms and signaling pathways implicated in mediating the effects of IL-6 on the expression of PPARα are limited. We previously revealed that IL-6 inhibits PPARα gene expression through CAAT/enhancer-binding protein transcription factors in hepatocytes. In this study, we determined that STAT1/3 was the direct downstream molecules that mediated the Janus kinase 2 (JAK2) and phosphatidylinositol-3 kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) signaling pathways in IL-6-induced repression of PPARα. Treatment of cells with pharmacological inhibitors of JAK2, PI3K, AKT, and mTOR attenuated the inhibitory effect of IL-6 on PPARα protein in a dose-dependent manner. These inhibitors also decreased the IL-6-induced repression of PPARα mRNA expression and promoter activity. Overexpression of STAT1 and STAT3 in HepG2 cells cotransfected with a reporter vector containing this PPARα promoter region revealed that both the expression plasmids inhibited the IL-6-induced repression of PPARα promoter activity. In the presence of inhibitors of JAK2 and mTOR (AG490 and rapamycin, respectively), IL-6-regulated protein expression and DNA binding of STAT1 and STAT3 were either completely or partially inhibited simultaneously, and the IL-6-induced repression of PPARα protein and mRNA was also inhibited. This study has unraveled novel pathways by which IL-6 inhibits PPARα gene transcription, involving the modulation of JAK2/STAT1-3 and PI3K/AKT/mTOR by inducing the binding of STAT1 and STAT3 to STAT-binding sites on the PPARα promoter. Together, these findings represent a new model of IL-6-induced suppression of PPARα expression by inducing STAT1 and STAT3 phosphorylation and subsequent down-regulation of PPARα mRNA expression.

Matched MeSH terms: Interleukin-6/pharmacology*