Stimulation of mucin exocytosis from human epithelial cells by nitric oxide: evidence for a cGMP-dependent and a cGMP-independent pathway

Branka, Jean-Eric; Vallette, G.; Jarry, Anne; Laboisse, Christian L.

doi:10.1042/bj3230521

Cited by 38 publications

(24 citation statements)

References 24 publications

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“…Goblet cells secrete mucin via an unregulated constitutive pathway that is dependent on the continuous movement of mucin granules from the Golgi apparatus to the apex of the cell and by a regulated process dependent on the sudden release of mucin from granules. This regulatory process is controlled by a wide variety of stimuli, including nerve activation and inflammatory mediators (6,31,33). In this study, we clearly demonstrated that leptin is one of these stimuli.…”

Section: Discussionmentioning

confidence: 65%

Luminal leptin activates mucin-secreting goblet cells in the large bowel

Plaisancié¹,

Ducroc²,

Homsi³

et al. 2006

American Journal of Physiology-Gastrointestinal and Liver Physi

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Leptin has been suggested to be involved in tissue injury and/or mucosal defence mechanisms. Here, we studied the effects of leptin on colonic mucus secretion and rat mucin 2 (rMuc2) expression. Wistar rats and ob/ ob mice were used. Secretion of mucus was followed in vivo in the rat perfused colon model. Mucus secretion was quantified by ELISA, and rMuc2 mRNA levels were quantified by real-time RT PCR. The effects of leptin alone or in association with protein kinase C (PKC) and phosphatidylinositol 3-kinase (PI3K) inhibitors on mucin secreted by human mucus-secreting HT29-MTX cells were determined. Leptin was detected in the rat colonic lumen at substantial levels. Luminal perfusion of leptin stimulates mucus-secreting goblet cells in a dose-dependent manner in vivo in the rat. Leptin (10 nmol/l) increased mucus secretion by a factor of 3.5 and doubled rMuc2 mRNA levels in the colonic mucosa. There was no damage to mucosa 24 h after leptin, but the number of stained mucus cells significantly increased. Leptin-deficient ob/ ob mice have abnormally dense mucus-filled goblet cells. In human colonic goblet-like HT29-MTX cells expressing leptin receptors, leptin increased mucin secretion by activating PKC- and PI3K-dependent pathways. This is the first demonstration that leptin, acting from the luminal side, controls the function of mucus-secreting goblet cells. Because the gel layer formed by mucus at the surface of the intestinal epithelium has a barrier function, our data may be relevant physiologically in defence mechanisms of the gastrointestinal tract.

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Section: Discussionmentioning

confidence: 65%

Luminal leptin activates mucin-secreting goblet cells in the large bowel

Plaisancié¹,

Ducroc²,

Homsi³

et al. 2006

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…PGE 2 increases intracellular cGMP content in rabbit gastric parietal cells, protecting the cells from injuries via activation of Cl Ϫ channels (26). cGMP also increases HCO 3 Ϫ secretion in bullfrog duodenum, which shows a protecting function from damage (8). These observations suggest that cGMP plays an important role in gastric cytoprotection.…”

Section: ϩmentioning

confidence: 64%

cGMP modulation of ACh-stimulated exocytosis in guinea pig antral mucous cells

Saad¹,

Shimamoto²,

Nakahari³

et al. 2006

American Journal of Physiology-Gastrointestinal and Liver Physi

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In guinea pig antral mucous cells, ACh stimulates the Ca2+-regulated exocytosis, which has a characteristics feature: an initial transient phase followed by a sustained phase. The effects of cGMP on ACh-stimulated exocytosis were studied in guinea pig antral mucous cells using video microscopy. cGMP enhanced the frequency of ACh-stimulated exocytotic events, whereas cGMP alone did not induce any exocytotic events under the ACh-unstimulated condition. cGMP did not stimulate either Ca2+ mobilization or cAMP accumulation. The Ca2+ dose-response studies demonstrated that cGMP shifted the dose-response curve upward with no shift to the lower concentration. This indicates that cGMP increased maximal responsiveness of the Ca2+-regulated exocytosis, but not the Ca2+ sensitivity. Moreover, under a condition of ATP depletion by dinitrophenol (DNP) or anoxia (N2 bubbling), ACh evoked only a sustained phase in exocytotic events with no initial transient phase. However, ACh evoked an initial transient phase followed by a sustained phase with addition of cGMP before ATP depletion, whereas only a sustained phase was evoked in a case of cGMP addition after ATP depletion. Thus cGMP-induced enhancement in ACh-stimulated exocytotic events requires ATP, suggesting that cGMP modulates ATP-dependent priming of Ca2+-regulated exocytosis in antral mucous cells. In conclusion, cGMP increases the number of primed granules via acceleration of the ATP-dependent priming, which enhances the Ca2+-regulated exocytosis stimulated by ACh.

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“…Other NO-dependent functions (including alterations in vasodilation, endothelial integrity, vascular adhesion, emigration of inflammatory cells, increased mucin secretion by goblet cells, altered intestinal smooth muscle function, and intestinal fluid secretion) may also play a role in the enteropathy accompanying parasite expulsion (29,50,53,(55)(56)(57). It has been suggested that a change in intestinal smooth muscle and fluid dynamics, which favors increased propulsion and fluid accumulation in the gut lumen, leads to the expulsion of loosely attached parasites (35).…”

Section: Discussionmentioning

confidence: 99%

Nitric Oxide Mediates Intestinal Pathology But Not Immune Expulsion DuringTrichinella spiralisInfection in Mice

Lawrence

Paterson

Wei

et al. 2000

The Journal of Immunology

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The relationship between intestinal pathology and immune expulsion of gastrointestinal (GI) nematodes remains controversial. Although immune expulsion of GI helminth parasites is usually associated with Th2 responses, the effector mechanisms directly responsible for parasite loss have not been identified. We have previously shown that while the intestinal pathology accompanying the expulsion of the GI parasite Trichinella spiralis may be dependent on IL-4 and mediated by TNF, parasite loss is independent of TNF. In contrast, intestinal pathology in other disease models has been attributed to Th1 cytokines, although it closely resembles that seen in helminth infections. Whereas production of inducible NO synthase (iNOS) in the gut is important for both homeostasis of the epithelial layer and in protection against pathogenic microorganisms, overproduction of NO has been implicated in the pathogenesis of a number of inflammatory conditions. We therefore investigated the role of NO in T. spiralis infection using iNOS-deficient mice. iNOS−/− and iNOS-/+ mice were infected with T. spiralis, and parasite expulsion and intestinal pathology were followed. Parasite expulsion proceeded similarly in both groups of animals, but significant intestinal pathology was only observed in the heterozygous mice. Thus it appears that, although the protective effects of Th2 responses in GI helminth infection do not require NO, this mediator contributes substantially to the associated enteropathy. NO may therefore be an important mediator of enteropathy in both Th1- and Th2-inducing conditions.

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Stimulation of mucin exocytosis from human epithelial cells by nitric oxide: evidence for a cGMP-dependent and a cGMP-independent pathway

Cited by 38 publications

References 24 publications

Luminal leptin activates mucin-secreting goblet cells in the large bowel

Luminal leptin activates mucin-secreting goblet cells in the large bowel

cGMP modulation of ACh-stimulated exocytosis in guinea pig antral mucous cells

Nitric Oxide Mediates Intestinal Pathology But Not Immune Expulsion DuringTrichinella spiralisInfection in Mice

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