Role of IL-6 in the resolution of pancreatitis in obese mice

IL‐6 contributes to the delayed resolution of inflammation and promotes a tumorgenic microenvironment in the pancreas of obese mice. Obesity increases severity of acute pancreatitis and risk of pancreatic cancer. Pancreatitis and obesity are associated with elevated IL‐6, a cytokine involved in infl...

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Bibliographic Details
Published in:Journal of leukocyte biology 2012-06, Vol.91 (6), p.957-966
Main Authors: Pini, Maria, Rhodes, Davina H., Castellanos, Karla J., Hall, Andrew R., Cabay, Robert J., Chennuri, Rohini, Grady, Eileen F., Fantuzzi, Giamila
Format: Article
Language:English
Subjects:
Animals
chemokines
Chemokines - blood
Chemokines - immunology
cytokines
inflammation
Inflammation - blood
Inflammation - immunology
Inflammation, Extracellular Mediators, & Effector Molecules
Interleukin-12 - blood
Interleukin-12 - immunology
Interleukin-18 - blood
Interleukin-18 - immunology
Interleukin-6 - blood
Interleukin-6 - immunology
Matrix Metalloproteinase 7 - metabolism
Mice
Mice, Knockout
Mice, Obese
MMP‐7
Obesity - blood
Obesity - immunology
Obesity - pathology
Pancreatitis - blood
Pancreatitis - immunology
Pancreatitis - pathology
STAT3 Transcription Factor - immunology
STAT3 Transcription Factor - metabolism
STAT‐3
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Summary:IL‐6 contributes to the delayed resolution of inflammation and promotes a tumorgenic microenvironment in the pancreas of obese mice. 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.
ISSN:0741-5400
1938-3673
DOI:10.1189/jlb.1211627