title: Leptin antagonist ameliorates chronic colitis in IL-10⁻/⁻ mice.
abstract: BACKGROUND
  Although the etiology of two major forms of inflammatory bowel disease (IBD), Crohn's disease (CD) and ulcerative colitis (UC) are unknown and evidence suggests that chronic intestinal inflammation is caused by an excessive immune response to mucosal antigens. Previous studies support the role for TGF-β1 through 3 in the initiation and maintenance of tolerance via the induction of regulatory T cells (Tregs) to control intestinal inflammation. Leptin, a satiety hormone produced primarily by adipose tissue, has been shown to increase during colitis progression and is believed to contribute to disease genesis and/or progression.
  
  
  OBJECTIVE
  We investigated the ability of a pegylated leptin antagonist (PG-MLA) to ameliorate the development of chronic experimental colitis.
  
  
  RESULTS
  Compared to vehicle control animals, PG-MLA treatment of mice resulted in an (1) attenuated clinical score; (2) reversed colitis-associated pathogenesis including a decrease in body weight; (3) reduced systemic and mucosal inflammatory cytokine expression; (4) increased insulin levels and (5) enhanced systemic and mucosal Tregs and CD39⁺ Tregs in mice with chronic colitis. The percentage of systemic and mucosal TGF-β1, -β2 and -β3 expressing CD4⁺ T cells were augmented after PG-MLA treatment. The activation of STAT1 and STAT3 and the expression of Smad7 were also reduced after PG-MLA treatment in the colitic mice. These findings clearly suggest that PG-MLA treatment reduces intestinal Smad7 expression, restores TGF-β1-3 signaling and reduces STAT1/STAT3 activation that may increase the number of Tregs to ameliorate chronic colitis.
  
  
  CONCLUSIONS
  This study clearly links inflammation with the metabolic hormone leptin suggesting that nutritional status influences immune tolerance through the induction of functional Tregs. Inhibiting leptin activity through PG-MLA might provide a new and novel therapeutic strategy for the treatment of IBD.
authors.affiliation: Pathology, Microbiology and Immunology, School of Medicine, University of South Carolina, Columbia, SC 29208, USA. Electronic address: Udai.singh@uscmed.sc.edu.
authors.forename: Udai P
authors.initials: UP
authors.lastname: Singh
authors.forename: Narendra P
authors.initials: NP
authors.lastname: Singh
authors.forename: Hongbing
authors.initials: H
authors.lastname: Guan
authors.forename: Brandon
authors.initials: B
authors.lastname: Busbee
authors.forename: Robert L
authors.initials: RL
authors.lastname: Price
authors.forename: Dennis D
authors.initials: DD
authors.lastname: Taub
authors.forename: Manoj K
authors.initials: MK
authors.lastname: Mishra
authors.forename: Raja
authors.initials: R
authors.lastname: Fayad
authors.forename: Mitzi
authors.initials: M
authors.lastname: Nagarkatti
authors.forename: Prakash S
authors.initials: PS
authors.lastname: Nagarkatti
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D001081:Apyrase / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects; D002908:Chronic Disease; D003092:Colitis / Q000188:drug therapy* / Q000276:immunology; D015536:Down-Regulation / Q000187:drug effects; D005260:Female; D007328:Insulin / Q000378:metabolism; D016753:Interleukin-10 / Q000235:genetics; D007413:Intestinal Mucosa / Q000187:drug effects* / Q000276:immunology; D020738:Leptin / Q000008:administration & dosage* / Q000031:analogs & derivatives* / Q000737:chemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011092:Polyethylene Glycols / Q000737:chemistry; D011994:Recombinant Proteins / Q000008:administration & dosage* / Q000737:chemistry; D050794:STAT1 Transcription Factor / Q000235:genetics / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D051906:Smad7 Protein / Q000235:genetics / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects* / Q000276:immunology; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D015703:Antigens, CD; D007328:Insulin; D020738:Leptin; D011994:Recombinant Proteins; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; D051906:Smad7 Protein; D016212:Transforming Growth Factor beta; C521086:murine leptin analog; D016753:Interleukin-10; D011092:Polyethylene Glycols; D001081:Apyrase; C067869:CD39 antigen
keywords: Antagonist; Crohn's disease (CD); Inflammation; Inflammatory bowel disease (IBD); Leptin; Pegylated; Ulcerative colitis (UC)