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PubMed2003

Identification of GM-CSF in Paneth cells using single-cell RT-PCR.

Paneth cells, granule-containing cells located at the bottom of the intestinal crypts, have a role in innate mucosal immunity. We identified the exclusive expression of granulocyte-macrophage colony-stimulating factor (GM-CSF) in Paneth cells using single-cell reverse transcription-polymerase chain reaction and cDNA array. Cytosolic total RNA was aspirated from single Paneth cells and other villous epithelial cells (non-Paneth cells) of rats using capillary micropipettes. In addition to lysozyme, secretory phospholipase A2, defensin, TNF-alpha, and xanthine dehydrogenase genes, cDNA array analysis revealed that the GM-CSF gene is specifically present in Paneth cells, whereas GM-CSF receptor beta-chain mRNA is expressed in Paneth cells and other epithelial cells. There was intense immunohistochemical staining of GM-CSF in Paneth cells but not in other epithelial cells. Treatment of IEC6 cells with GM-CSF enhanced expression of CD80 and CD86. Thus, GM-CSF in Paneth cells might have an important role in mucosal immunity through increasing the expression of costimulatory molecules in epithelial cells.

Animals↗
PubMed1981

The stem-cell zone of the small intestinal epithelium. II. Evidence from paneth cells in the newborn mouse.

The restriction of Paneth cell formation to the top of the Paneth cell distribution in the adult was suggested to be due either to the existence of a stem-cell zone or to the influence of a Paneth cell population-density gradient (Bjerkness and Cheng, 1981). To distinguish between the two possible mechanisms, the development of the Paneth cell distribution in neonatal mice (0-10 days old) was studied. If restricted formation were due to the presence of a population-density gradient of Paneth cells, then in neonatal animals, in the absence of a Paneth cell population-density gradient, Paneth cell formation would occur throughout the crypt base. If, on the other hand, restricted formation were due to the presence of a stem-cell zone, and if this mechanism were operative in the newborn, Paneth cell formation in the newborn would be restricted to the region above the stem-cell zone. The position of each Paneth cell within the crypt, and the size of its largest granule, were recorded. On day 0, Paneth cells were present, but crypts were poorly developed and positional assignment was not possible. On day 1, immature crypts developed. All Paneth cells found in immature crypts on day 1 were at the crypt-surface junction (approximately position 5). On day 2, most Paneth cells were at the crypt-surface junction. Thereafter, Paneth cells began to appear at lower positions. On day 3, there were 15 times more Paneth cells in position 5 than in position 1. On day 4, there were still three times more Paneth cells in position 5 than in position 1. With age, the proportion of Paneth cells in position 1 increased while that in position 5 decreased. On day 10 there were more Paneth cells in position 1 than in 5. At all time intervals, granules of Paneth cells in position 1 were significantly larger than those in position 5, indicating that Paneth cells in position 1 were older than those in position 5. It was concluded that in the neonate, before the establishment of a Paneth cell population-density gradient, Paneth cell formation was restricted to positions 5 and above. This supports the existence of a stem-cell zone, not a Paneth cell population-density gradient, as the underlying mechanism of restricted Paneth cell formation in the adult.

Aging↗
PubMed1989

Effects of cholecystokinin and carbamylcholine on Paneth cell secretion in mice: a comparison with pancreatic acinar cells.

To confirm whether the Paneth cells of mice (ICR, male, 10-12 weeks old) have the same secretory response to hormonal and cholinergic stimulation as do pancreatic acinar cells, ultrastructural changes of Paneth cells and pancreatic acinar cells 1 hr after administration of various doses of cholecystokinin (octapeptide, CCK-8) and carbamylcholine were morphometrically assessed. After maximal (1.5 micrograms/kg intraperitoneally [i.p.]) and supramaximal (15 micrograms/kg, i.p.) stimulation by CCK-8, pancreatic acinar cells showed, respectively, degranulation or disturbance of secretion (e.g., an increase in lysosome-like bodies, aggregation of zymogen granules). The Paneth cells, however, were almost unchanged in the parameters examined. After carbamylcholine injection (1,000 micrograms/kg, subcutaneously [s.c.]), both pancreatic acinar cells and Paneth cells showed degranulation. Paneth cells sometimes developed large vacuoles, probably formed after massive exocytosis; such vacuoles were not observed in pancreatic acinar cells. It is suggested that Paneth cells and pancreatic acinar cells have different secretory responses. Paneth cell secretion, which possibly plays a role in controlling the intestinal bacterial milieu, may be stimulated by cholinergic rather than hormonal mechanisms.

Animals↗
PubMed1984

Trypsin-like immunoreactivity in human Paneth cells.

Human intestinal Paneth cells characterized by their content of lysozyme were shown to contain cationic trypsin immunoreactivity. This trypsin-like immunoreactivity was shown in the Paneth cells at their normal localization at the basis of the crypts of Lieberkühn and also in Paneth cells of metaplastic areas in gastric mucosa. This original finding is a further indication of a resemblance between Paneth and acinar pancreatic cells.

Duodenum↗
PubMed1992

Bethanechol and a G-protein activator, NaF/AlCl3, induce secretory response in Paneth cells of mouse intestine.

Paneth cells located at the bottom of intestinal crypts may play a role in controlling the bacterial milieu of the intestine. Using morphometry to clarify the secretory mechanism of the Paneth cells, we studied the ultrastructural changes in mouse Paneth cells produced following intra-arterial perfusion with Hanks' balanced salt solution containing a cholinergic muscarinic secretagogue (bethanechol), a neuroblocking agent (tetrodotoxin), or a G-protein activator (NAF/AlCl3). Bethanechol (2 x 10(-4) mol/l) induced Paneth-cell secretion. Many Paneth cells massively exocytosed their secretory material into the crypt lumen; the enhanced secretion caused degranulation and vacuole formation. However, tetrodotoxin (2 x 10(-6) mol/l) did not prevent the bethanechol-enhanced secretion by the Paneth cells. NaF (1 x 10(-2) mol/l) and AlCl3 (1 x 10(-5) mol/l) induced massive exocytosis of the Paneth cells; the exocytotic figures were similar to those observed in mice stimulated by bethanechol. G-protein activation was followed by a sequence of intracellular events, resulting in exocytosis.

Aluminum↗
PubMed1997

Examining the role of Paneth cells in the small intestine by lineage ablation in transgenic mice.

The Paneth cell lineage is one of four epithelial lineages derived from the adult mouse small intestine's multipotent stem cell. Mature Paneth cells secrete antimicrobial peptides (cryptdins), growth factors, as well as two gene products, a secreted phospholipase A2 and matrilysin, that has been implicated as modifiers of adenoma formation in mice containing a mutation in the tumor suppressor Apc. Immature Paneth cells are located just above and below the cell layer, in intestinal crypts, that has been proposed to contain the multipotent stem cell. Paneth cells differentiate during a downward migration to the crypt base. The location and direction of Paneth cell migration, their high density and long residency time at the crypt base, and the nature of their secreted gene products, suggest that they may influence the structure and/or function of the stem cell niche. Paneth cell ablation can therefore be viewed as an experimental manipulation of the cellular microenvironment that purportedly contains the stem cell and its immediate descendants. Two types of ablation experiments were performed in transgenic mice. Nucleotides -6500 to +34 of the mouse cryptdin-2 gene (CR2) were used to express an attenuated diphtheria toxin A fragment. Light and electron microscopic immunohistochemical analyses of several pedigrees of postnatal day 28 to 180 animals established that ablation of Paneth cells is accompanied by an increase in the proportion of undifferentiated crypt base columnar cells. These cells normally co-exist with Paneth cells. The ablation does not produce a detectable effect on the proliferation or terminal differentiation programs of the other three lineages or on host-microbial interactions. The last conclusion is based on the ability of crypts to remain free of microbes detectable by Gram and Warthin-Starry stains and by retention of the normal crypt-villus distribution of components of the diffuse gut-associated lymphoid tissue. CR2-directed expression of simian virus 40 large T antigen also results in a loss of mature Paneth cells but produces a marked amplification of crypt cells having a morphology intermediate between Paneth and granule goblet cells. EM immunohistochemical analyses suggest that intermediate cells can differentiate to mature goblet cells but not to Paneth cells, as they migrate up the crypt-villus axis. Our findings suggest that (i) stemness in the crypt is not defined by instructive interactions involving the Paneth cell; (ii) expressing a Paneth cell fate may require that precursors migrate to the crypt base; (iii) antimicrobial factors produced by Paneth cells are not required to prevent colonization of small intestinal crypts; and (iv) this lineage does not function to maintain the asymmetric crypt-villus distribution of components of the diffuse gut-associated lymphoid tissue.

Animals↗
PubMed1981

The stem-cell zone of the small intestinal epithelium. I. Evidence from Paneth cells in the adult mouse.

Stem cells in the small intestinal epithelium are known to differentiate into columnar, mucous, enteroendocrine, and Paneth cells. However, the site of initiation of stem-cell differentiation has been unknown. To approach this problem we determined the site of stem-cell differentiation along the Paneth cell line, using light microscopic morphometry and radioautography. The smallest Paneth cells containing the smallest granules were in positions 6 and 7, while the largest ones containing the largest granules were in positions 1 and 2 at the base of the crypt. Paneth cell death was less prevalent above position 3 than it was in position 1. Since cell size, granule size, and cell death are indicators of Paneth cell age, it was deduced that there is a gradient of Paneth cell age in the crypt base, with the oldest Paneth cells at the bottom, and the youngest at the top. After single injection or continuous infusion of 3H-thymidine, the first labeled Paneth cells to appear were the highest Paneth cells in their crypt column. Later, labeled Paneth cells became more prevalent in lower positions, and, eventually, appeared in position 1. The size of granules in labeled Paneth cells increased with time. It was concluded that Paneth cells originate in position 5 or above and then migrate downward. These results are consistent with a stem-cell zone hypothesis, which proposes that stem cells in positions 1-4 receive no inducement to differentiate. Only those stem cells that migrate up out of the stem-cell zone into position 5 will be induced and then begin to differentiate.

Animals↗
PubMed1999

Peptide localization and gene structure of cryptdin 4, a differentially expressed mouse paneth cell alpha-defensin.

Paneth cells in crypts of the small intestine express antimicrobial peptides, including alpha-defensins, termed cryptdins in mice. Of the known Paneth cell alpha-defensins, the cryptdin 4 gene is unique, because it is inactive in the duodenum and expressed at maximal levels in the distal small bowel (D. Darmoul and A. J. Ouellette, Am. J. Physiol. 271:G68-G74, 1996). With a cryptdin 4-specific antibody, immunohistochemical staining of ileal Paneth cells was strong and specific for cytoplasmic granules, demonstrating that this microbicidal peptide is a secretory product of Paneth cells in the distal small intestine. Consistent with the pattern of cryptdin 4 mRNA distribution along the length of the gut, the cryptdin 4 peptide was not detected in duodenum. Structurally, the cryptdin 4 gene resembles other Paneth cell alpha-defensin genes. Its two exons, transcriptional start site, intron, splice sites, and 3' flanking sequences are characteristic of the highly conserved mouse alpha-defensin genes. However, in the region upstream of the transcriptional initiation site, the cryptdin 4 gene contains a repeated 130-bp element that is unique to this alpha-defensin gene. Every independent cryptdin 4 genomic clone examined carries the repeated element, which contains putative recognition sequences for TF-IID-EIIA, cMyc-RS-1, and IgHC.2/CuE1.1; the repeat proximal to the start of transcription replaces DNA at the corresponding position in other mouse alpha-defensin genes. We speculate that this unique duplicated element may have a cis-acting regulatory role in the positional specificity of cryptdin 4 gene expression.

Amino Acid Sequence↗
PubMed1981

Lysozyme in neoplastic Paneth cells of a jejunal adenocarcinoma.

This is the first reported case in which neoplastic cells not of granulocytic or monocytic origin have been shown to contain lysozyme. A highly differentiated metastasizing adenocarcinoma of the jejunum is presented. Areas of the tumour contained cells resembling Paneth cells, that is, they contained cytoplasmic granules with 1) stained red with Masson's trichrome and 2) were shown to contain lysozyme by an immunoperoxidase technique. No argentaffin cells could be identified within the tumour. Staining of mucosubstance revealed large intestine-type sulfated glycoproteins in the tumour tissue. The presence of lysozyme-containing neoplastic Paneth cells suggests that the tumor: 1) originated from the mucosal crypts, and 2) had a high degree of cellular differentiation.

Adenocarcinoma↗
PubMed2001

Identification of xanthine dehydrogenase/xanthine oxidase as a rat Paneth cell zinc-binding protein.

Paneth cells are zinc-containing cells localized in small intestinal crypts, but their function has not been fully elucidated. Previously, we showed that an intravenous injection of diphenylthiocarbazone (dithizone), a zinc chelator, induced selective killing of Paneth cells, and purified a zinc-binding protein in Paneth cells. In the present study, we further characterized one of these proteins, named zinc-binding protein of Paneth cells (ZBPP)-1. Partial amino acid sequences of ZBPP-1 showed identity with rat xanthine dehydrogenase (XD)/xanthine oxidase (XO). Anti-rat XD antibody (Ab) recognized ZBPP-1, and conversely anti ZBPP-1 Ab recognized 85 kDa fragment of rat XD in Western blotting. Messenger RNA and protein levels of XD were consistent with our previous data on the fluctuation of Paneth cell population after dithizone injection. Thus, ZBPP-1 is an 85 kDa fragment of XD/XO in Paneth cells. XD/XO in Paneth cells may play important roles in intestinal function.

Animals↗
PubMed1997

N- and O-linked oligosaccharides in the secretory granules of rat Paneth cells: an ultrastructural cytochemical study.

Paneth cells are located at the base of the intestinal glands. The origin, composition, and function of these cells have not been well established. The sharing of a common pathway of development with the goblet cells has been suggested. The aim of the present study was to explore the cytochemical composition of rat Paneth cells and to discuss a possible developmental relationship between goblet and Paneth cells. Lectins (WGA, LTA, UEA-1, AAA, and HPA) were used as a precise tool for the ultrastructural localization of carbohydrates. Several procedures were performed in combination with lectin cytochemistry: beta-elimination, a reaction that specifically removes O-linked oligosaccharides (typical of mucin-type glycoproteins of goblet cells); and treatment with peptide N-glycosidase F, an enzyme that removes N-linked oligosaccharides from glycoproteins. Secretory granules of Paneth cells showed a biphasic nature composed of an electron-lucent peripheral halo containing O-linked oligosaccharides with GalNAc and GlcNAc residues and N-linked oligosaccharides with GlcNAc residues (only sparse Fuc residues were scarcely identified in O-linked oligosaccharides), and an electron-dense core containing N- and O-linked oligosaccharides with Fuc residues. Neither GlcNAc nor GalNAc was identified. The occurrence of O-linked oligosaccharides in the Paneth cells and the biphasic nature of the secretory granules, similar to that of transitional cells intermediate between mucous and serous cells of other tissues, favor the hypothesis of a common lineage for goblet and Paneth cells.

Acetylgalactosamine↗
PubMed1989

A method of quantitating Paneth cell metaplasia of the stomach by image analysis.

Paneth cells are one of the histologic components of intestinal metaplasia of the stomach, as are mucin-producing goblet cells. With the aid of an image quantifier, the distribution of Paneth cells histochemically labeled with acid fuchsin was analyzed for a gastrectomy specimen containing an adenocarcinoma of the intestinal type; the topographic distribution of goblet cells histochemically labeled with Alcian blue (pH 2.5) was also analyzed. The specimen was cut into 63 blocks (0.5 X 4.0 cm) in four zones; antrum (zone I), intermediate region (zone II) and fundus (zones III and IV). Paneth cells were found only in sections containing mucin-producing goblet cells. Paneth cells were found in 12.5% of the 16 sections from the antral zone I containing Alcian blue-positive goblet cells. The rates were 44.4% for the intermediate zone II and 55.5% for the distal fundic zone III. The total area occupied by Paneth cells was significantly lower in the gastric mucosa as compared to the duodenal mucosa. The "Paneth cell index" (total Paneth cell area/total goblet cell area) was highest in the duodenum, followed by the distal fundic zone III. This method of quantitating Paneth cell metaplasia of the stomach will be used to investigate the topographic distribution of those cells in populations with low and high incidences of intestinal metaplasia.

Adenocarcinoma↗
PubMed2004

Enhanced expression of transforming growth factor-beta1 in inflammatory cells and secretory granules in Paneth cells in the small intestine of mice infected with Toxocara canis.

The small intestine is the initial organ which Toxocara canis larvae invade. Information on intestinal pathological changes associated with transforming growth factor-beta1 (TGF-beta1) and secretory granules (SG) in Paneth cells (PCs) caused by T. canis is unclear. Mice orally inoculated with 250 T. canis infective eggs were evaluated by pathological and immunohistochemical assessments with a 294-day investigation. Pathologically, the inflammatory reactions with or without trapped larvae in the submucosa were observed only within the first 28 days post-infection (DPI), with inflammatory injury ranging from severe during 2 DPI to mild between 7 and 28 DPI. The crypts of Leiberkuhn were major larval penetration sites. Enhanced expression of SG in PCs appeared earlier than those of TGF-beta1 in infiltrating cells. The significance of both effectors might be related to the host's defense against larval invasion in the intestinal phase of toxocaral infection.

Animals↗
PubMed2003

Enteric salmonella infection inhibits Paneth cell antimicrobial peptide expression.

Paneth cells, highly secretory epithelial cells found at the bases of small intestinal crypts, release a variety of microbicidal molecules, including alpha-defensins and lysozyme. The secretion of antimicrobials by Paneth cells is thought to be important in mucosal host defense against invasion by enteric pathogens. We explored whether enteric pathogens can interfere with this arm of defense. We found that oral inoculation of mice with wild-type Salmonella enterica serovar Typhimurium decreases the expression of alpha-defensins (called cryptdins in mice) and lysozyme. Oral inoculation with Salmonella serovar Typhimurium strains that are heat killed, lack the PhoP regulon, and lack the SPI1 type III secretion system or with Listeria monocytogenes does not have this effect. Salmonella may gain a specific survival advantage in the intestinal lumen by decreasing the expression of microbicidal peptides in Paneth cells through direct interactions between Salmonella and the small intestinal epithelium.

Animals↗
PubMed1978

Paneth cells in Barrett's esophagus.

Paneth cells were identified in esophageal biopsies from 4 patients with Barrett's epithelium of the specialized columnar type. These cells were identical to human intestinal Paneth cells by light microscopy, electron microscopy, and histochemical staining reactions. Retrospective review of biopsies from 8 additional cases with esophageal specialized columnar epithelium yielded 2 further cases with Paneth cells. The presence of Paneth cells, along with goblet cells, suggests that specialized columnar type epithelium in the esophagus may be a form of highly differentiated intestinalization.

Epithelial Cells↗
PubMedDate not supplied

Paneth cell adenoma of the ileum.

A Paneth cell adenoma of the ileum was recently found in a 47-year-old male with familial adenomatous polyposis (FAP). The patient had years previously been subjected to a total proctocolectomy. Following surgery, endoscopical biopsies were obtained from the duodenum (10 biopsies) in four instances and from the ileal pouch (6 biopsies) in three. All biopsies were taken between 1988 and 2003. Hematoxylin and eosin (H&E) sections from all those 16 biopsies were reviewed. In one biopsy from the ileal pouch, a tubular adenoma carrying 92% dysplastic Paneth cells was found. Paneth cells were more easily singled out when H&E sections were observed in a fluorescent microscope than when using conventional transmitted light, or lysozyme immunostain. Despite a wide distribution of Paneth cells in mucosas with intestinal metaplasia (e.g. Barrett's esophagus and gastric intestinal metaplasia), in the normal small intestine and in the large intestine with chronic inflammatory diseases only a few Paneth cell neoplasias have been reported in the GI tract. The cause of the apparent natural resistance of these specialized cells provided with anti-microbial and growth factors to undergo neoplastic transformation deserve further investigation. A review of the literature indicates that this is the first reported case of Paneth cell adenoma of the small intestine.

Adenomatous Polyposis Coli↗
PubMed2003

Crohn's disease and the NOD2 gene: a role for paneth cells.

BACKGROUND & AIMS: The NOD2 gene, which is strongly associated with susceptibility to Crohn's disease (CD) of the terminal ileum, interacts with bacterial lipopolysaccharide (LPS), inducing cellular activation. However, the mechanisms by which NOD2 mutations cause terminal ileitis are unknown, and NOD2 is expressed most highly by peripheral blood monocytes, which are distributed ubiquitously and readily respond to LPS via cell-surface receptors. Paneth cells on the other hand, are most numerous in the terminal ileum, are critically important in enteric antibacterial defense, and respond to LPS through as yet undefined pathways. We therefore determined if these specialized intestinal epithelial cells also expressed the NOD2 gene. METHODS: In situ hybridization, immunohistochemistry, and laser-capture microdissection were used to determine RNA and protein expression in tissue sections, and real-time reverse-transcription polymerase chain reaction (RT-PCR) was used to quantitate gene expression in intestinal epithelial cells and peripheral blood mononuclear cells. RESULTS: NOD2 was detected readily in monocytes, but not in mature macrophages in the lamina propria or within granulomas, and levels declined as monocytes differentiated into macrophages in vitro, so that Caco-2 cells expressed more NOD2 mRNA than macrophages. NOD2 mRNA was enriched in crypts compared with villi, and in situ, Paneth cells were the most prominent cells expressing NOD2 in normal and CD-affected intestinal tissue, where they also strongly expressed tumor necrosis factor alpha (TNFalpha) RNA. CONCLUSIONS: The NOD2 gene product is most abundant in Paneth cells in the terminal ileum, which could therefore play a critical and hitherto unrecognized role in the pathogenesis of NOD2-associated CD.

Caco-2 Cells↗