title: Leptin Promotes cPLA₂ Gene Expression through Activation of the MAPK/NF-κB/p300 Cascade.
abstract: Hyperplasia or hypertrophy of adipose tissues plays a crucial role in obesity, which is accompanied by the release of leptin. Recently, obesity was determined to be associated with various pulmonary diseases including asthma, acute lung injury, and chronic obstructive pulmonary disease. However, how obesity contributes to pulmonary diseases and whether leptin directly regulates lung inflammation remains unclear. We used cell and animal models to study the mechanisms of leptin mediation of pulmonary inflammation. We found that leptin activated de novo synthesis of cytosolic phospholipase A₂-α (cPLA₂-α) in vitro in the lung alveolar type II cells, A549, and in vivo in ICR mice. Upregulated cPLA₂-α protein was attenuated by pretreatment with an OB-R blocking antibody, U0126, SB202190, SP600125, Bay11-7086, garcinol, and p300 siRNA, suggesting roles of p42/p44 MAPK, p38 MAPK, JNK1/2, NF-κB, and p300 in leptin effects. Leptin enhanced the activities of p42/p44 MAPK, p38 MAPK, JNK1/2, and p65 NF-κB in a time-dependent manner. Additional studies have suggested the participation of OB-R, p42/p44 MAPK, and JNK1/2 in leptin-increased p65 phosphorylation. Furthermore, p300 phosphorylation and histone H4 acetylation were reduced by blockage of OB-R, p42/p44 MAPK, p38 MAPK, JNK1/2, and NF-κB in leptin-stimulated cells. Similarly, blockage of the MAPKs/NF-κB/p300 cascade significantly inhibited leptin-mediated cPLA₂-α mRNA expression. Our data as a whole showed that leptin contributed to lung cPLA₂-α expression through OB-R-dependent activation of the MAPKs/NF-κB/p300 cascade.
authors.affiliation: Division of Chest Medicine, Shin Kong Wu Ho-Su Memorial Hospital, Taipei 11101, Taiwan. pack14tw@gmail.com.
authors.forename: Pei-Sung
authors.initials: PS
authors.lastname: Hsu
authors.affiliation: Graduate Institute of Basic Medicine, Fu Jen Catholic University, Xinzhuang 24205, Taiwan. leo-wu@livemail.tw.
authors.forename: Chi-Sheng
authors.initials: CS
authors.lastname: Wu
authors.affiliation: Department of Internal Medicine, En-Chu-Kong Hospital, Sanxia 23702, Taiwan. cjf6699@yahoo.com.tw.|PhD Program in Nutrition and Food Science, Fu Jen Catholic University, Xinzhuang 24205, Taiwan. cjf6699@yahoo.com.tw.
authors.forename: Jia-Feng
authors.initials: JF
authors.lastname: Chang
authors.affiliation: Graduate Institute of Basic Medicine, Fu Jen Catholic University, Xinzhuang 24205, Taiwan. 081551@mail.fju.edu.tw.
authors.forename: Wei-Ning
authors.initials: WN
authors.lastname: Lin
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D050881:E1A-Associated p300 Protein / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects*; D054513:Group IV Phospholipases A2 / Q000235:genetics*; D006801:Humans; D020738:Leptin / Q000494:pharmacology*; D008297:Male; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D020738:Leptin; D016328:NF-kappa B; D050881:E1A-Associated p300 Protein; D020928:Mitogen-Activated Protein Kinases; D054513:Group IV Phospholipases A2
keywords: MAPK; NF-κB; inflammation; leptin; p300