Resistin-like molecule beta regulates intestinal mucous secretion and curtails TNBS-induced colitis in mice.
BACKGROUND
Resistin and resistin-like molecule (RELM)beta comprise a novel class of cysteine-rich proteins secreted into the circulation implicated in hepatic insulin resistance and inflammation. RELMbeta is specifically produced by intestinal goblet cells but regulation of its expression and much of its local function are not elucidated. RELMbeta has been suggested to regulate colonic inflammation susceptibility, which is dependent on the mucosal barrier integrity.


METHODS
In this work we explored the physiopathological role of RELMbeta in the colon. Among agents tested, carbachol and gastrin were strong inhibitors of RELMbeta mRNA accumulation. We examined the effect of recombinant RELMbeta on mucin secretion by human mucus-secreting HT29-Cl.16E cells in culture and by mouse colonic goblet cells in vivo.


RESULTS
RELMbeta upregulated MUC2 and M1/MUC5AC gene expression in HT29-Cl.16E cells. RELMbeta enhanced M1/MUC5AC secretion by human colonic HT29-Cl.16E cells and MUC2 secretion by murine intestinal goblet cells. RELMbeta exerted its action exclusively on the apical side of HT29-Cl.16E cells, in agreement with its luminal mucosecretagogue effect in mice. Its action required calcium, protein kinase C, tyrosine kinases, and extracellular-regulated protein kinase activities and was synergized by carbachol. An intracolonic RELMbeta challenge was performed in the trinitrobenzene sulfonic acid (TNBS)-murine model of colitis and macroscopic and histological scores were monitored. The macroscopic and histopathological severity of TNBS-induced colitis was significantly attenuated by RELMbeta pretreatment.


CONCLUSIONS
A direct participation in maintaining the mucosal defense barrier can be ascribed to RELMbeta in line with a regulatory role in intestinal inflammation.
Krimi
Rim Belharbi
RB
INSERM, U773, Centre de Recherche Biomédicale Bichat Beaujon CRB3, Paris, France.
Kotelevets
Larissa
L
Dubuquoy
Laurent
L
Plaisancié
Pascale
P
Walker
Francine
F
Lehy
Thérèse
T
Desreumaux
Pierre
P
Van Seuningen
Isabelle
I
Chastre
Eric
E
Forgue-Lafitte
Marie-Elisabeth
ME
Marie
Jean-Claude
JC
D000818:Animals; D015153:Blotting, Western; D002118:Calcium / Q000502:physiology; D002217:Carbachol / Q000494:pharmacology; D002478:Cells, Cultured; D003092:Colitis / Q000139:chemically induced / Q000473:pathology / Q000503:physiopathology*; D005755:Gastrins / Q000494:pharmacology; D015870:Gene Expression; D020397:Goblet Cells / Q000378:metabolism; D006729:Hormones, Ectopic / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D007413:Intestinal Mucosa / Q000378:metabolism*; D007422:Intestines; D051379:Mice; D055271:Mucin 5AC; D055262:Mucin-2; D009077:Mucins / Q000235:genetics; D009093:Mucus / Q000378:metabolism*; D011493:Protein Kinase C / Q000502:physiology; D011494:Protein Kinases / Q000502:physiology; D011505:Protein-Tyrosine Kinases / Q000502:physiology; D012333:RNA, Messenger / Q000187:drug effects; D011994:Recombinant Proteins / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014302:Trinitrobenzenesulfonic Acid
D005755:Gastrins; D006729:Hormones, Ectopic; D036341:Intercellular Signaling Peptides and Proteins; C524625:MUC2 protein, human; C524678:MUC5AC protein, human; C524626:Muc2 protein, mouse; C524679:Muc5ac protein, mouse; D055271:Mucin 5AC; D055262:Mucin-2; D009077:Mucins; D012333:RNA, Messenger; D011994:Recombinant Proteins; C486522:Retnlb protein, mouse; D014302:Trinitrobenzenesulfonic Acid; D002217:Carbachol; D011494:Protein Kinases; D011505:Protein-Tyrosine Kinases; D011493:Protein Kinase C; D002118:Calcium