Dextran sulfate sodium-induced murine colitis activates NF-kappaB and increases galanin-1 receptor expression.
Galanin is widely distributed in enteric nerve terminals and acts to modulate intestinal motility by altering smooth muscle contraction. This ligand causes Cl(-) secretion when colonic epithelial cells express the galanin-1 receptor (Gal1-R) subtype. Because Gal1-R expression by colonic epithelia is upregulated by the transcription factor nuclear factor-kappaB (NF-kappaB), increasingly appreciated as critical in the pathophysiology of inflammatory bowel disease, we wondered whether the diarrhea associated with this condition could be due to NF-kappaB-mediated increases in Gal1-R expression. To test this hypothesis, we provided oral dextran sulfate sodium (DSS) to C57BL/6J mice. Although Gal1-R are not normally expressed by epithelial cells lining the mouse colon, DSS treatment resulted in increased NF-kappaB activation and Gal1-R expression. Whereas galanin had no effect on murine colonic tissues studied ex vivo, it progressively increased short-circuit current and colonic fluid secretion in DSS-treated mice. Concomitant parenteral administration of the NF-kappaB inhibitor dexamethasone attenuated the activation of this transcription factor by DSS, inhibiting the increase in Gal1-R expression. Although Gal1-R-specific antagonists do not exist, intracolonic administration of commercially available galanin antibody diminished the DSS-induced increase in colonic fluid accumulation. Overall, these data demonstrate that a significant component of the excessive fluid secretion observed in DSS-treated mice is due to increased Gal1-R expression.
Marrero
J A
JA
Department of Medicine, University of Illinois at Chicago and Chicago Veterans Affairs Medical Center, West Side Division, Chicago, Illinois 60612, USA.
Matkowskyj
K A
KA
Yung
K
K
Hecht
G
G
Benya
R V
RV
D000818:Animals; D003092:Colitis / Q000139:chemically induced / Q000378:metabolism* / Q000503:physiopathology; D003106:Colon / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D016264:Dextran Sulfate / Q000633:toxicity*; D019004:Galanin / Q000494:pharmacology; D005786:Gene Expression Regulation; D007249:Inflammation; D015212:Inflammatory Bowel Diseases / Q000473:pathology / Q000503:physiopathology; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism*; D044088:Receptors, Galanin; D018013:Receptors, Neuropeptide / Q000235:genetics*
D016328:NF-kappa B; D044088:Receptors, Galanin; D018013:Receptors, Neuropeptide; D019004:Galanin; D016264:Dextran Sulfate