Blunted activation of NF-kappaB and NF-kappaB-dependent gene expression by geranylgeranylacetone: involvement of unfolded protein response.
Geranylgeranylacetone (GGA), an anti-ulcer agent, has anti-inflammatory potential against experimental colitis and ischemia-induced renal inflammation. However, molecular mechanisms involved in its anti-inflammatory effects are largely unknown. We found that, in glomerular mesangial cells, GGA blocked activation of nuclear factor-kappaB and consequent induction of monocyte chemoattractant protein 1 (MCP-1) by inflammatory cytokines. It was inversely correlated with induction of unfolded protein response (UPR) evidenced by expression of 78kDa glucose-regulated protein (GRP78) and suppression of endoplasmic reticulum stress-responsive alkaline phosphatase. Various inducers of UPR including tunicamycin, thapsigargin, A23187, 2-deoxyglucose, dithiothreitol, and AB(5) subtilase cytotoxin reproduced the suppressive effects of GGA. Furthermore, attenuation of UPR by stable transfection with GRP78 diminished the anti-inflammatory effects of GGA. These results disclosed a novel, UPR-dependent mechanism underlying the anti-inflammatory potential of GGA.
Hayakawa
Kunihiro
K
Department of Molecular Signaling, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Chuo, Yamanashi 409-3898, Japan.
Hiramatsu
Nobuhiko
N
Okamura
Maro
M
Yao
Jian
J
Paton
Adrienne W
AW
Paton
James C
JC
Kitamura
Masanori
M
D000818:Animals; D000897:Anti-Ulcer Agents / Q000494:pharmacology*; D018932:Chemokine CCL2 / Q000378:metabolism; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004224:Diterpenes / Q000494:pharmacology*; D000091342:Endoplasmic Reticulum Chaperone BiP; D004722:Endoribonucleases / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects*; D006801:Humans; D053583:Interleukin-1beta / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D050527:Mesangial Cells; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011489:Protein Denaturation; D017510:Protein Folding; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D051381:Rats; D011994:Recombinant Proteins / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D000897:Anti-Ulcer Agents; C491766:Ccl2 protein, rat; D018932:Chemokine CCL2; D016207:Cytokines; D004224:Diterpenes; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D053583:Interleukin-1beta; D008565:Membrane Proteins; D016328:NF-kappa B; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; C403982:ERN2 protein, human; D017346:Protein Serine-Threonine Kinases; D004722:Endoribonucleases; C031049:geranylgeranylacetone