Role of leptin receptor-induced STAT3 signaling in modulation of intestinal and hepatic inflammation in mice.
Leptin-deficient ob/ob mice are resistant to dextran sulfate sodium (DSS)-induced colitis and Concanavalin A (Con A)-induced hepatitis. However, the signal transduction pathways involved have not been identified. The present study investigated the effect of leptin-induced STAT3 signaling in the DSS and Con A models. Mice carrying a leptin receptor (LEPR) gene mutant for Y1138 (s/s mice), with abrogated leptin-induced STAT3 signaling, were compared with wild-type (WT) and LEPR-deficient db/db mice. Administration of DSS to s/s mice resulted in a clinical score and colon shortening of intermediate severity compared with disease induced in WT and db/db mice-the latter group having the lowest disease severity. A comparable degree of inflammatory infiltrate and epithelial damage was observed in the colon of WT and s/s mice, and these parameters were reduced in db/db mice. Levels of IFN-gamma, IL-6, IL-10, and TNF-alpha were comparable in the colon of s/s and db/db mice, and a similar trend was observed for CXCL2. s/s and WT mice developed severe liver disease in response to Con A, whereas db/db mice were protected. However, Con A-induced serum IL-6 and TNF-alpha levels in s/s mice mimicked levels observed in db/db rather than WT mice. In conclusion, lack of leptin-induced STAT3 signaling is associated with reduced cytokine production following DSS and Con A administration, but it appears to sensitize mice to the effects of proinflammatory mediators.
Gove
Melissa E
ME
Kinesiology and Nutrition Department, University of Illinois at Chicago, Chicago, IL 60612, USA.
Rhodes
Davina H
DH
Pini
Maria
M
van Baal
Jantine W
JW
Sennello
Joseph A
JA
Fayad
Raja
R
Cabay
Robert J
RJ
Myers
Martin G
MG
Fantuzzi
Giamila
G
D000818:Animals; D056486:Chemical and Drug Induced Liver Injury / Q000473:pathology*; D003092:Colitis / Q000139:chemically induced / Q000473:pathology*; D003208:Concanavalin A / Q000009:adverse effects; D016207:Cytokines / Q000096:biosynthesis; D016264:Dextran Sulfate / Q000009:adverse effects; D007249:Inflammation / Q000139:chemically induced / Q000276:immunology*; D051379:Mice; D054411:Receptors, Leptin / Q000502:physiology*; D050796:STAT3 Transcription Factor / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*
D016207:Cytokines; D054411:Receptors, Leptin; D050796:STAT3 Transcription Factor; D003208:Concanavalin A; D016264:Dextran Sulfate