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Suppressive Effects of Imidapril on Th1- and Th2-Related Chemokines in Monocytes
  1. Ming-Kai Tsai, MD*†,
  2. Ren-Long Jan, MD,
  3. Ching-Hsiung Lin, MD§∥,
  4. Chang-Hung Kuo, MD¶**,
  5. San-Nan Yang, MD, PhD¶**††,
  6. Huan-Nan Chen, MS**,
  7. Ming-Yii Huang, MD, PhD‡‡§§,
  8. Chih-Hsing Hung, MD, PhD¶**††∥∥
  1. From the *Division of Nephrology, Department of Internal Medicine, Kaohsiung Armed Forces General Hospital, Kaohsiung; †Department of Nursing, MeiHo University, Pingtung; ‡Department of Pediatrics, Chi Mei Medical Center, Liouying; §Division of Chest Medicine and ∥Asthma Center, Changhua Christian Hospital, Changhua; ¶Graduate Institute of Medicine, College of Medicine, **Department of Pediatrics, Kaohsiung Medical University Hospital, ††Department of Pediatrics, Faculty of Pediatrics, College of Medicine, ‡‡Department of Radiation Oncology, Kaohsiung Medical University Hospital, and §§Department of Radiation Oncology, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung; and ∥∥Department of Pediatrics, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung, Taiwan.
  1. Received February 7, 2011, and in revised form June 19, 2011.
  2. Accepted for publication June 20, 2011.
  3. Reprints: Chih-Hsing Hung, MD, PhD, Department of Pediatrics, Kaohsiung Medical University Hospital, Kaohsiung Medical University, No. 100, Tz-You 1st Rd, Kaohsiung 807, Taiwan. E-mail: pedhung{at}gmail.com.
  4. This study was supported by grants from Medical Research Fund (no. 9905) of Kaohsiung Armed Forces General Hospital and from National Science Council (NSC 99-2314-B-037-014-MY3) of the Republic of China.
  5. Ming-Kai Tsai and Ren-Long Jan contributed equally to this work.
  6. The authors declare no conflicts of interest.

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.

Key Words
  • imidapril
  • TNF-α
  • IP-10
  • I-309
  • monocyte
  • JNK

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