title: Role of IL-6 in the resolution of pancreatitis in obese mice.
abstract: Obesity increases severity of acute pancreatitis and risk of pancreatic cancer. Pancreatitis and obesity are associated with elevated IL-6, a cytokine involved in inflammation and tumorigenesis. We studied the role of IL-6 in the response of lean and obese mice to pancreatitis induced by IL-12 + IL-18. Lean and diet-induced obese (DIO) WT and IL-6 KO mice and ob/ob mice pretreated with anti-IL-6 antibodies were evaluated at Days 1, 7, and 15 after induction of pancreatitis. Prolonged elevation of IL-6 in serum and visceral adipose tissue was observed in DIO versus lean WT mice, whereas circulating sIL-6R declined in DIO but not lean mice with pancreatitis. The severe inflammation and lethality of DIO mice were also observed in IL-6 KO mice. However, the delayed resolution of neutrophil infiltration; sustained production of CXCL1, CXCL2, and CCL2; prolonged activation of STAT-3; and induction of MMP-7 in the pancreas, as well as heightened induction of serum amylase A of DIO mice, were blunted significantly in DIO IL-6 KO mice. In DIO mice, production of OPN and TIMP-1 was increased for a prolonged period, and this was mediated by IL-6 in the liver but not the pancreas. Results obtained in IL-6 KO mice were confirmed in ob/ob mice pretreated with anti-IL-6 antibodies. In conclusion, IL-6 does not contribute to the increased severity of pancreatitis of obese mice but participates in delayed recovery from acute inflammation and may favor development of a protumorigenic environment through prolonged activation of STAT-3, induction of MMP-7, and sustained production of chemokines.
authors.affiliation: Department of Kinesiology and Nutrition, University of Illinois at Chicago, Chicago, IL, USA.
authors.forename: Maria
authors.initials: M
authors.lastname: Pini
authors.forename: Davina H
authors.initials: DH
authors.lastname: Rhodes
authors.forename: Karla J
authors.initials: KJ
authors.lastname: Castellanos
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Hall
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Cabay
authors.forename: Rohini
authors.initials: R
authors.lastname: Chennuri
authors.forename: Eileen F
authors.initials: EF
authors.lastname: Grady
authors.forename: Giamila
authors.initials: G
authors.lastname: Fantuzzi
mesh_terms: D000818:Animals; D018925:Chemokines / Q000097:blood / Q000276:immunology; D007249:Inflammation / Q000097:blood / Q000276:immunology; D018664:Interleukin-12 / Q000097:blood / Q000276:immunology; D020382:Interleukin-18 / Q000097:blood / Q000276:immunology; D015850:Interleukin-6 / Q000097:blood / Q000276:immunology*; D020783:Matrix Metalloproteinase 7 / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008820:Mice, Obese; D009765:Obesity / Q000097:blood / Q000276:immunology* / Q000473:pathology; D010195:Pancreatitis / Q000097:blood / Q000276:immunology* / Q000473:pathology; D050796:STAT3 Transcription Factor / Q000276:immunology / Q000378:metabolism
chemical_list: D018925:Chemokines; D020382:Interleukin-18; D015850:Interleukin-6; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D018664:Interleukin-12; D020783:Matrix Metalloproteinase 7