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Effect of Prostaglandin I2 Analogs on Macrophage Inflammatory Protein 1α in Human Monocytes Via I Prostanoid Receptor and Cyclic Adenosine Monophosphate
  1. Ming-Kai Tsai, MD*†,
  2. Chong-Chao Hsieh, MD,
  3. Hsuan-Fu Kuo, MD§,
  4. San-Nan Yang, MD, PhD∥¶,
  5. Chang-Hung Kuo, MD**††‡‡,
  6. Ming-Yii Huang, MD, PhD§§,
  7. Ying-Ming Tsai, MD∥∥,
  8. Min-Sheng Lee, MD††‡‡,
  9. 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; ‡Division of Cardiac Surgery, Department of Surgery, §Division of Cardiology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University; ∥Department of Pediatrics, E-DA Hospital, I-Shou University; ¶Department of Marine Biotechnology and Resources, National Sun Yat-sen University; **Graduate Institute of Medicine, College of Medicine, ††Department of Pediatrics, Kaohsiung Medical University Hospital, and Department of Pediatrics, Faculty of Pediatrics, College of Medicine, Kaohsiung Medical University; ‡‡Department of Pediatrics, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung; §§Department of Radiation Oncology, ∥∥Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Kaohsiung Medical University, and ¶¶Department of Pediatrics, Kaohsiung Municipal Hsiao-Kang Hospital, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan, Republic of China.
  1. Received May 6, 2013, and in revised form November 2, 2013.
  2. Accepted for publication November 19, 2013.
  3. Reprints: Chih-Hsing Hung, MD, PhD, Department of Pediatrics, Kaohsiung Medical University Hospital, Kaohsiung Medical University, #100, Tz-You 1st Rd, Kaohsiung 807, Taiwan, Republic of China. E-mail: pedhung{at}gmail.com.
  4. M.-K.T., C.-C.H., M.-S.L., and C.-H.H. contributed equally to this work.
  5. This study was supported by grants from Medical Research Fund (no. 101-06 and 101-03) of Kaohsiung Armed Forces General Hospital and from National Science Council (NSC 99-2314-B-037-014-MY3) of the Republic of China and a grant from Kaohsiung Municipal Ta-Tung Hospital KMTTH-101-007.

Abstract

Aims Inflammation plays critical roles in atherosclerosis. Chemokines are responsible for leukocyte trafficking and involve in inflammatory diseases. Macrophage inflammatory protein 1α (MIP-1α) has been implicated in atherosclerotic lesion formation. Prostaglandin I2 (PGI2) analog, used in pulmonary hypertension, has been reported to have anti-inflammatory functions. However, little is known about its role in the MIP-1α production in human monocytes.

Methods We investigated the effects of 3 conventional (iloprost, beraprost, and treprostinil) and 1 new (ONO-1301) PGI2 analogs, on the expression of MIP-1α expression in human monocytes. Human primary monocytes from control subjects and THP-1 cell line were treated with PGI2 analogs, with or without lipopolysaccharide (LPS) stimulation. Supernatants were harvested to measure MIP-1α levels by enzyme-linked immunosorbent assay. To explore which receptors involved the effects of PGI2 analogs on the expression of MIP-1α expression, I prostanoid (IP) and E prostanoid, peroxisome proliferator-activated receptor (PPAR)-α, and PPAR-r receptor antagonists were used to pretreat THP-1 cells. Forskolin, a cyclic adenosine monophosphate (cAMP) activator, was also used to further confirm the cAMP involvement on the effect of PGI2 analogs in MIP-1α production.

Results Three PGI2 analogs could suppress LPS-induced MIP-1α production in THP-1 cells and human primary monocytes. ONO-1301 had a similar effect. CAY 10449, an IP receptor antagonist, could reverse the suppressive effects on MIP-1α production of iloprost. Forskolin, a cAMP activator, also suppressed MIP-1α production in THP-1 cells.

Conclusions Prostaglandin I2 analogs suppressed LPS-induced MIP-1α production in human monocytes via the IP receptor and cAMP pathway. The PGI2 analog may be potential in the treatment for atherosclerosis.

Key Words
  • PGI2
  • MIP-1α
  • iloprost
  • monocyte
  • beraprost
  • atherosclerosis

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