title: Inhibition of SAPK/JNK leads to enhanced IL-1-induced IL-6 synthesis in osteoblasts.
abstract: Stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK)(1) which belongs to the MAP kinase superfamily regulates many cellular events. We previously reported that interleukin 1 (IL-1) stimulates the synthesis of interleukin 6 (IL-6) through activation of ERK and p38 MAP kinase in osteoblast-like MC3T3-E1 cells, and that AMP-activated protein kinase (AMPK) negatively regulates the IL-1-induced IL-6 synthesis through IκB/NF-κB pathway. In the present study, we investigated the role of SAPK/JNK in the IL-1-stimulated IL-6 synthesis in these cells. IL-1 induced the phosphorylation of SAPK/JNK. SP600125, an inhibitor of SAPK/JNK, increased the release and the mRNA expression levels of IL-6 induced by IL-1. IL-1-stimulated IL-6 release was significantly up-regulated in SAPK/JNK-knocked down cells. SP600125 remarkably suppressed the IL-1-induced phosphorylation of both IκB and NF-κB, whereas SP600125 failed to affect the IL-1-induced phosphorylation of AMPK, STAT3 or Src. Compound C, an AMPK inhibitor, attenuated the IL-1-induced phosphorylation of SAPK/JNK. SP600125 enhanced IL-1-stimulated IL-6 release also in normal human osteoblasts. These results strongly suggest that SAPK/JNK negatively regulates IL-1-stimulated IL-6 synthesis and acts at the point between AMPK and IκB/NF-κB in osteoblasts.
authors.affiliation: Department of Orthopedic Surgery, Nagoya City University Graduate School of Medical Sciences, Nagoya 467-8601, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Kondo
authors.forename: Takanobu
authors.initials: T
authors.lastname: Otsuka
authors.forename: Rie
authors.initials: R
authors.lastname: Matsushima-Nishiwaki
authors.forename: Gen
authors.initials: G
authors.lastname: Kuroyanagi
authors.forename: Jun
authors.initials: J
authors.lastname: Mizutani
authors.forename: Ikuo
authors.initials: I
authors.lastname: Wada
authors.forename: Osamu
authors.initials: O
authors.lastname: Kozawa
authors.forename: Haruhiko
authors.initials: H
authors.lastname: Tokuda
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D000873:Anthracenes / Q000494:pharmacology; D002460:Cell Line; D055785:Gene Knockdown Techniques; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D007375:Interleukin-1 / Q000494:pharmacology*; D015850:Interleukin-6 / Q000096:biosynthesis* / Q000235:genetics; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D010006:Osteoblasts / Q000187:drug effects / Q000378:metabolism*; D010766:Phosphorylation; D011720:Pyrazoles / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis; D034741:RNA, Small Interfering / Q000235:genetics; D050796:STAT3 Transcription Factor / Q000378:metabolism; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D000873:Anthracenes; D020672:I-kappa B Proteins; D007375:Interleukin-1; D015850:Interleukin-6; D016328:NF-kappa B; D011720:Pyrazoles; D011743:Pyrimidines; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D050796:STAT3 Transcription Factor; C516138:dorsomorphin; C432165:pyrazolanthrone; D019061:src-Family Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D055372:AMP-Activated Protein Kinases