Suppression of constitutive but not Il-1beta-inducible expression of monocyte chemoattractant protein-1 in mesangial cells by retinoic acids: intervention in the activator protein-1 pathway.
Retinoic acid regulates a wide range of biologic processes, including inflammation. This study investigated the effect of all-trans-retinoic acid (t-RA) on the constitutive and cytokine-inducible expression of monocyte chemoattractant protein 1 (MCP-1) in rat mesangial cells. Serum-deprived mesangial cells exhibited substantial levels of MCP-1 mRNA, and the expression was markedly upregulated by interleukin-1beta (IL-1beta). Pretreatment with t-RA abrogated the constitutive mRNA expression but did not inhibit the IL-1beta-inducible expression. The similar effects were observed by 9-cis-RA. The suppressive effect of t-RA required retinoic acid receptors. t-RA did not affect the stability of MCP-1 mRNA, indicating that its suppressive effect was at the transcriptional level. Experiments that used pharmacologic and genetic inhibitors showed that the IL-1beta-inducible MCP-1 expression was dependent on nuclear factor-kappaB (NF-kappaB) and independent of activator protein 1 (AP-1). In contrast, the constitutive expression of MCP-1 was dependent on both NF-kappaB and AP-1. t-RA substantially inhibited the constitutive activity of AP-1 but did not inhibit NF-kappaB activity in mesangial cells. These data suggested that (1) constitutive and IL-1beta-inducible expression of MCP-1 was differently regulated by AP-1 and NF-kappaB and (2) t-RA inhibited selectively the constitutive expression of MCP-1 via intervention in the AP-1 pathway.
Department of Medicine, Royal Free and University College Medical School, University College London, Jules Thorn Institute, Middlesex Hospital, London, United Kingdom.|Departamento de Fisiologia, Facultad de Medicina, Universidad de Alcala, Alcala de Henares, Madrid, Spain.
Javier
J
Lucio-Cazana
Department of Medicine, Royal Free and University College Medical School, University College London, Jules Thorn Institute, Middlesex Hospital, London, United Kingdom.
Kenji
K
Nakayama
Department of Medicine, Royal Free and University College Medical School, University College London, Jules Thorn Institute, Middlesex Hospital, London, United Kingdom.
Qihe
Q
Xu
Department of Medicine, Royal Free and University College Medical School, University College London, Jules Thorn Institute, Middlesex Hospital, London, United Kingdom.
Tsuneo
T
Konta
Department of Medicine, Royal Free and University College Medical School, University College London, Jules Thorn Institute, Middlesex Hospital, London, United Kingdom.|Departamento de Fisiologia, Facultad de Medicina, Universidad de Alcala, Alcala de Henares, Madrid, Spain.
Victoria
V
Moreno-Manzano
Department of Medicine, Royal Free and University College Medical School, University College London, Jules Thorn Institute, Middlesex Hospital, London, United Kingdom.
Akira
A
Furusu
Department of Medicine, Royal Free and University College Medical School, University College London, Jules Thorn Institute, Middlesex Hospital, London, United Kingdom.
Masanori
M
Kitamura
D000077556:Alitretinoin; D000818:Animals; D018932:Chemokine CCL2 / Q000037:antagonists & inhibitors* / Q000235:genetics; D005920:Glomerular Mesangium / Q000166:cytology / Q000378:metabolism*; D007375:Interleukin-1 / Q000494:pharmacology*; D008297:Male; D016328:NF-kappa B / Q000502:physiology; D020871:RNA Stability; D012333:RNA, Messenger / Q000737:chemistry; D051381:Rats; D017207:Rats, Sprague-Dawley; D018168:Receptors, Retinoic Acid / Q000502:physiology; D018808:Transcription Factor AP-1 / Q000502:physiology; D014212:Tretinoin / Q000494:pharmacology*
D018932:Chemokine CCL2; D007375:Interleukin-1; D016328:NF-kappa B; D012333:RNA, Messenger; D018168:Receptors, Retinoic Acid; D018808:Transcription Factor AP-1; D000077556:Alitretinoin; D014212:Tretinoin