Bone-derived SDF-1 stimulates IL-6 release via CXCR4, ERK and NF-kappaB pathways and promotes osteoclastogenesis in human oral cancer cells.
Oral squamous cell carcinoma (SCC) has a striking tendency to invade to bone. The chemokine stromal cell-derived factor-1 (SDF-1) is constitutively secreted by osteoblasts and plays a key role in homing of hematopoietic cells to the bone marrow. Interleukin (IL)-6 plays an important role in osteoclastogenesis. Herein, we found that SDF-1 alpha increased the secretion of IL-6 in cultured human SCC cells, as shown by reverse transcriptase-polymerase chain reaction and enzyme-linked immunosorbent assay. SDF-1 alpha also increased the surface expression of chemokine receptor 4 (CXCR4) in SCC cells. CXCR4-neutralizing antibody, CXCR4-specific inhibitor (AMD3100) or small interfering RNA against CXCR4 inhibited SDF-1 alpha-induced increase IL-6 production. The transcriptional regulation of IL-6 by SDF-1 alpha was mediated by phosphorylation of extracellular signal-regulated kinases (ERKs) and activation of the nuclear factor-kappa B (NF-kappaB) components p65 and p50. The binding of p65 and p50 to the NF-kappaB element on the IL-6 promoter was enhanced by SDF-1 alpha. In addition, IL-6 antibody antagonized the SCC-conditioned medium-increased osteoclastogenesis. These results suggested that SDF-1 alpha from osteoblasts could induce release of IL-6 in human SCC cells via activation of CXCR4, ERK and NF-kappaB pathway and thereby promote osteoclastogenesis.
Tang
Chih-Hsin
CH
Department of Pharmacology, China Medical University, Taichung 404, Taiwan. chtang@mail.cmu.edu.tw
Chuang
Jing-Yuan
JY
Fong
Yi-Chin
YC
Maa
Ming-Chei
MC
Way
Tzong-Der
TD
Hung
Chien-Hui
CH
D001859:Bone Neoplasms / Q000556:secondary*; D001842:Bone and Bones / Q000502:physiology*; D002294:Carcinoma, Squamous Cell; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D054377:Chemokine CXCL12 / Q000502:physiology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism*; D009062:Mouth Neoplasms / Q000473:pathology*; D016328:NF-kappa B / Q000502:physiology*; D010006:Osteoblasts / Q000502:physiology*; D010010:Osteoclasts / Q000166:cytology; D010012:Osteogenesis; D012516:Osteosarcoma; D053245:RANK Ligand / Q000502:physiology; D012333:RNA, Messenger / Q000235:genetics; D019718:Receptors, CXCR4 / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction
C527276:CXCR4 protein, human; D054377:Chemokine CXCL12; D015850:Interleukin-6; D016328:NF-kappa B; D053245:RANK Ligand; D012333:RNA, Messenger; D019718:Receptors, CXCR4; D048049:Extracellular Signal-Regulated MAP Kinases