Guanosine 3',5'-cyclic monophosphate (cGMP)/cGMP-dependent protein kinase induce interleukin-6 transcription in osteoblasts.

Abstract

Natriuretic peptides and nitric oxide (NO) activate the cGMP/cGMP-dependent protein kinase (PKG) signaling pathway and play an important role in bone development and adult bone homeostasis. The cytokine IL-6 regulates bone turnover and osteoclast and osteoblast differentiation. We found that C-type natriuretic peptide and the NO donor Deta-NONOate induced IL-6 mRNA expression in primary human osteoblasts, an effect mimicked by the membrane-permeable cGMP analog 8-chlorophenylthio-cGMP (8-CPT-cGMP). Similar results were obtained in rat UMR106 osteosarcoma cells, where C-type natriuretic peptide and 8-CPT-cGMP stimulated transcription of the human IL-6 promoter and increased IL-6 secretion into the medium. Cotransfection of type I PKG enhanced the cGMP effect on the IL-6 promoter, whereas small interfering RNA-mediated silencing of PKG I expression prevented the cGMP effect on IL-6 mRNA expression. Step-wise deletion of the IL-6 promoter demonstrated a cAMP response element to be critical for transcriptional effects of cGMP, and experiments with dominant interfering proteins showed that cGMP activation of the promoter required cAMP response element binding-related proteins, and, to a lesser extent, proteins of the CAAT enhancer-binding protein and activator protein-1 (Fos/Jun) families. 8-CPT-cGMP induced nuclear translocation of type I PKG and increased cAMP response element binding-related protein phosphorylation on Ser(133). PKG regulation of the IL-6 promoter appeared to be of physiological significance, because inhibitors of the NO/cGMP/PKG signaling pathway largely prevented fluid shear stress-induced increases of IL-6 mRNA in UMR106 cells.

• Authors: Kate E Broderick, Tong Zhang, Hema Rangaswami, Ying Zeng, Xin Zhao, Gerry R Boss, Renate B Pilz
• Journal: Molecular endocrinology (Baltimore, Md.) (Mol Endocrinol) Vol. 21 Issue 5 Pg. 1148-62 (May 2007) ISSN: 0888-8809 [Print] United States
• PMID: 17341596 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Interleukin-6
• RNA, Messenger
• Nitric Oxide
• Cyclic GMP-Dependent Protein Kinases
• Cyclic GMP

Topics

• Animals
• Bone Neoplasms
• Cell Differentiation
• Cell Line, Tumor
• Cyclic GMP (metabolism)
• Cyclic GMP-Dependent Protein Kinases (genetics, metabolism)
• Genes, Reporter
• Humans
• Interleukin-6 (genetics)
• Nitric Oxide (pharmacology)
• Osteoblasts (cytology, drug effects, physiology)
• Osteosarcoma
• Promoter Regions, Genetic
• RNA, Messenger (genetics)
• Rats
• Reverse Transcriptase Polymerase Chain Reaction
• Transcription, Genetic
• Transfection