title: Suppressive effects of imidapril on Th1- and Th2-related chemokines in monocytes.
abstract: BACKGROUND
  Angiotensin-converting enzyme inhibitors (ACEIs) are used to control hypertension and are superior to other antihypertensive agents in protecting the progressive deterioration of autoimmune-related nephritis. An imbalance of T helper 1 (Th1)/Th2 is thought to contribute to the pathogenesis of autoimmune diseases and their related glomerulonephritis. I-309 is a Th2-related chemokine involved in the recruitment of Th2 cells toward Th2-related inflammation. Tumor necrosis factor α (TNF-α) and Th1-related chemokines, interferon-inducible protein 10 (IP-10)/CXCL10 are also involved in autoimmune glomerulonephritis. However, the modulatory effects and the mechanisms of ACEIs on TNF-α and Th1- and Th2-related chemokines in monocytes remain poorly defined.
  
  
  OBJECTIVE
  We investigated the effects of imidapril and perindopril, 2 ACEIs, on the expression of IP-10, I-309, and TNF-α in human monocytes and also the associated intracellular mechanism.
  
  
  RESULTS
  Imidapril and perindopril significantly downregulated lipopolysaccharide (LPS)-induced TNF-α, I-309, and IP-10 in THP-1 cells and human primary monocytes. All 3 mitogen-activated protein kinase inhibitors suppressed LPS-induced TNF-α and I-309 expression in human primary monocytes. Only extracellular signal-regulated kinases and c-Jun N-terminal kinases (JNK) mitogen-activated protein kinase inhibitors suppressed LPS-induced IP-10 expression. Lipopolysaccharide-induced mitogen-activated protein kinase kinase 4 (MKK4), p-JNK, and c-Jun expression in human primary monocytes was suppressed by imidapril.
  
  
  CONCLUSIONS
  These data demonstrate that ACEI is effective in downregulating LPS-induced TNF-α, I-309, and IP-10, which play important roles in the pathogenesis of inflammation. Its suppressive effect on TNF-α, I-309, and IP-10 may, at least in part, involve the down-regulation of LPS-induced MKK4-JNK-c-Jun expression.
authors.affiliation: Division of Nephrology, Department of Internal Medicine, Kaohsiung Armed Forces General Hospital, Kaohsiung, Taiwan.
authors.forename: Ming-Kai
authors.initials: MK
authors.lastname: Tsai
authors.forename: Ren-Long
authors.initials: RL
authors.lastname: Jan
authors.forename: Ching-Hsiung
authors.initials: CH
authors.lastname: Lin
authors.forename: Chang-Hung
authors.initials: CH
authors.lastname: Kuo
authors.forename: San-Nan
authors.initials: SN
authors.lastname: Yang
authors.forename: Huan-Nan
authors.initials: HN
authors.lastname: Chen
authors.forename: Ming-Yii
authors.initials: MY
authors.lastname: Huang
authors.forename: Chih-Hsing
authors.initials: CH
authors.lastname: Hung
mesh_terms: D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D054402:Chemokine CCL1 / Q000096:biosynthesis; D054357:Chemokine CXCL10 / Q000096:biosynthesis; D018925:Chemokines / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism; D015536:Down-Regulation; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D006801:Humans; D048289:Imidazolidines / Q000494:pharmacology*; D007249:Inflammation; D008070:Lipopolysaccharides / Q000378:metabolism; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D020935:MAP Kinase Signaling System; D009000:Monocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D018417:Th1 Cells / Q000166:cytology*; D018418:Th2 Cells / Q000166:cytology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D054402:Chemokine CCL1; D054357:Chemokine CXCL10; D018925:Chemokines; D016207:Cytokines; D048289:Imidazolidines; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; C065166:imidapril; D048670:MAP Kinase Kinase 4; C482559:MAP2K4 protein, human