title: Prostaglandin I(2) analogues suppress TNF-α expression in human monocytes via mitogen-activated protein kinase pathway.
abstract: OBJECTIVE
  Although treatment for asthma control has improved a lot recently, refractory asthma is still a challenge for clinicians. Evidence revealed that anti-tumor necrosis factor (TNF)-α therapy may have potential in treating refractory asthma. Recently in an animal model, prostaglandin I(2) (PGI(2)) analogues can suppress the cardinal feature of asthma. However, whether PGI(2) analogues can regulate TNF-α expression in monocytes and the mechanism is not well-known.
  
  
  METHODS
  The human monocytes were pretreated with beraprost, iloprost and treprostinil, three PGI(2) analogues, before stimulation with lipopolysaccharide (LPS). TNF-α concentration of the cell supernatants was measured by ELISA. Intracellular signaling was investigated by Western blot.
  
  
  RESULTS
  PGI(2) analogues suppressed LPS-induced TNF-α expression in THP-1 cells. CAY10449, an I prostanoid receptor antagonist, could reverse these effects. Beraprost increased intracellular cAMP level in THP1 cells. Forskolin, an adenylyl cyclase activator, could confer similar effect. LPS-induced TNF-α expression in THP-1 cells could be reversed by mitogen-activator protein kinase (MAPK)-p38, extracellular signal-related kinase (ERK) and c-Jun N-terminal kinase (JNK) inhibitors. Western blot revealed that beraprost suppressed MAPK phospho-p38, phosphor-JNK and phosphor-ERK expression.
  
  
  CONCLUSIONS
  PGI(2) analogues suppressed LPS-induced TNF-α expression in THP-1 cells via the IP receptor-cAMP and the MAPK pathways. PGI(2) analogues may have potentiality to treat asthma.
authors.affiliation: Department of Emergency Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Wei-Li
authors.initials: WL
authors.lastname: Wang
authors.forename: Chang-Hung
authors.initials: CH
authors.lastname: Kuo
authors.forename: Yu-Te
authors.initials: YT
authors.lastname: Chu
authors.forename: Ching-Hua
authors.initials: CH
authors.lastname: Huang
authors.forename: Ka-Pan
authors.initials: KP
authors.lastname: Lam
authors.forename: Shau-Ku
authors.initials: SK
authors.lastname: Huang
authors.forename: Yuh-Jyh
authors.initials: YJ
authors.lastname: Jong
authors.forename: Yu-Ting
authors.initials: YT
authors.lastname: Kuo
authors.forename: Chih-Hsing
authors.initials: CH
authors.lastname: Hung
mesh_terms: D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D002460:Cell Line; D011464:Epoprostenol / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D016285:Iloprost / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000502:physiology*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009000:Monocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D047495:PPAR gamma / Q000037:antagonists & inhibitors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D000959:Antihypertensive Agents; D047495:PPAR gamma; D014409:Tumor Necrosis Factor-alpha; D014665:Vasodilator Agents; C048081:beraprost; D011464:Epoprostenol; D020928:Mitogen-Activated Protein Kinases; D016285:Iloprost; C427248:treprostinil