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PubMed1993

A Paneth cell specific zinc-binding protein in the rat. Purification and immunohistochemical localization.

BACKGROUND: Paneth cells are zinc-containing cells widely distributed in Lieberkühn's crypts of small intestine in many species, but their function has remained obscure. Our previous study showed that a single intravenous injection of diphenylthiocarbazone (dithizone), a zinc chelator, forms zinc-dithizonate complexes in the cytoplasm of Paneth cells to ensure rapid and selective killing of the cells. EXPERIMENTAL DESIGN: To verify the proteins that selectively deleted from intestinal mucosa after dithizone treatment, intestinal proteins from the rats with or without dithizone injection were compared in sodium dodecyl sulfate-polyacrylamide gel electrophoresis. One such protein, a 90 kilodalton (kd) protein, was purified to homogeneity from normal rat intestine. A polyclonal antiserum was prepared by immunizing a rabbit with purified 90 kd protein to use in immunohistochemical study. RESULTS: Among several proteins deleted after dithizone injection, a 90 kd protein with an isoelectric point of 5.9 +/- 0.2, was purified to homogeneity from normal intestine by a combination of zinc affinity column and electroelution. Immunohistochemistry with rabbit anti-90 kd antiserum showed that the cytoplasmic granules in Paneth cells were stained. After dithizone administration, the 90 kd protein containing cells rapidly disappeared, but resumed as Paneth cells regenerated. Also positively stained with this antibody were a few mononuclear cells broadly distributed in the lamina propria of the digestive tract, but they were not affected by dithizone treatment. CONCLUSIONS: A 90 kd zinc-binding protein was identified and purified from rat Paneth cells that was deleted in dithizone-treated rat intestine. We propose to designate it as a zinc-binding protein of Paneth cell.

Animals↗
PubMed2005

Wnt signalling induces maturation of Paneth cells in intestinal crypts.

Wnt signalling, which is transduced through beta-catenin/TCF4, maintains the undifferentiated state of intestinal crypt progenitor cells. Mutational activation of the pathway initiates the adenomacarcinoma sequence. Whereas all other differentiated epithelial cells migrate from the crypt onto the villus, Paneth cells home towards the source of Wnt signals--that is, the crypt bottom. Here, we show that expression of a Paneth gene programme is critically dependent on TCF4 in embryonic intestine. Moreover, conditional deletion of the Wnt receptor Frizzled-5 abrogates expression of these genes in Paneth cells in the adult intestine. Conversely, adenomas in Apc-mutant mice and colorectal cancers in humans inappropriately express these Paneth-cell genes. These observations imply that Wnt signals in the crypt can separately drive a stem-cell/progenitor gene programme and a Paneth-cell maturation programme. In intestinal cancer, both gene programmes are activated simultaneously.

Animals↗
PubMed1986

Quantitative light microscopic observations on Paneth cells of germ-free and ex-germ-free Wistar rats.

Germ-free rats were inoculated with bacteria from feces of SPF rats, and the Paneth cells in the ileal crypts were observed at different time intervals after inoculation. 12 h after inoculation, the Paneth cells showed a striking degranulation and the occurrence of supranuclear vacuoles. The Paneth cell area was significantly reduced. Four days to 3 weeks after inoculation, the secretory granules of Paneth cells were abundant, and both number and area of Paneth cells showed a progressive increase coming close to the data in SPF rats. The present study demonstrates interrelationships between secretory activity of Paneth cells and the microbial milieu in the small intestine and that the presently used experimental model is well suited for examining the histophysiology of Paneth cells. Moreover, the results suggest that Paneth cell numbers may also be closely related to crypt length.

Animals↗
PubMed1980

Ultrastructural changes in Paneth cells during hibernation in the ground squirrel Spermophilus lateralis.

The ultrastructure of Paneth cells from jejuno-ileal segments of the small intestine of the ground squirrel, S. lateralis, was examined under normal euthermic conditions and during the profoundly depressed metabolic conditions of natural hibernation. Paneth cells obtained from hibernating animals gave evidence of markedly reduced activity when compared to Paneth cells from euthermic animals. In hibernating animals, the nuclei were smaller, with less prominent nucleoli and with an increased proportion of heterochromatin, In hibernating animals, the rough endoplasmic reticulum was fragmentary and poorly organized, in contrast to the typical arrangement of concentric lamellae seen in euthermic animals. Although the total number of ribosomes was decreased in hibernating animals, there were proportionally more free ribosomes than in euthermic animals. Paneth cells from hibernating animals also contained a greater number of apical secretory granules which were smaller and more variable in electron density than granules from control animals. These ultrastructural features indicate that during hibernation the Paneth cell is relatively quiescent.

Animals↗
PubMed1994

Expression of pokeweed lectin binding in murine intestinal Paneth cells.

Pokeweed (Phytolacca americana) lectin was found to stain the secretory granules in epithelial Paneth cells of small intestine in mice and rats. The distribution of Paneth cells stained with this lectin was identical to that obtained by another immunohistochemical marker for lysozyme. However, in comparison with other immunohistochemical markers, Pokeweed lectin is a more robust method for identifying Paneth cells in histological sections and for studying their secretory granules. Co-expression of the Pokeweed lectin binding sites in some oligomucous cells within the crypts suggested a close developmental link between these two cell types. Only one other non-epithelial cell type was stained by this lectin, and these were migratory lymphocytes found within the villus epithelium and lamina propria. Approximately 20% of these lymphocyte cells were also positive for the expression of CD3+. Pokeweed lectin was therefore used to study changes in the frequency of Paneth cells and intra-epithelial lymphocytes in normal and immunologically compromised animals (following infection with a parasite worm Trichuris muris and in a model of graft-versus-host rejection). This study confirmed that the population of Paneth cells turns over slowly even during conditions of inflammation.

Animals↗
PubMed1990

Tumor necrosis factor mRNA localized to Paneth cells of normal murine intestinal epithelium by in situ hybridization.

Paneth cells in normal murine small intestine contain TNF mRNA that is readily detectable by in situ hybridization, unlike resident macrophages in lamina propria, which are negative. Northern blot analysis of whole tissue shows the presence of mRNA that has the same electrophoretic mobility as TNF mRNA from activated macrophages. A low level of TNF bioactivity, but no immunoreactivity, was detected in normal small intestine, and TNF production in resting Paneth cells appears to be post-transcriptionally controlled. Typical leukocyte surface membrane markers were not found on Paneth cells, but were expressed by the surrounding lamina propria macrophages. Paneth cells are thus epithelial cells with leukocyte-like secretory potential that may be important in intestinal physiology and pathology.

Animals↗
PubMed1996

Paneth cells express high levels of CD95 ligand transcripts: a unique property among gastrointestinal epithelia.

CD95 (APO-1/Fas), a cell surface receptor and member of the tumor necrosis factor receptor superfamily, induces apoptosis upon oligomerization. CD95 is broadly expressed in normal tissues. The CD95 ligand (CD95L) is a member of the tumor necrosis factor family of cytokines and exists in a membrane-bound and in a soluble form. In vitro, CD95L is expressed and released by activated T lymphocytes. The range of cell types capable of expressing CD95L in vivo is unknown so far. Using a specific probe for human CD95L and sensitive in situ hybridization, we examined CD95L mRNA expression along the gastrointestinal tract. The scarce lymphohistiocytic infiltrate within the lamina propria contained small subsets of medium-sized labeled cells, some of which bad short cytoplasmic protrusions and others of which were lymphoid in morphology. Autochthonous cells of the gastrointestinal tract did not contain any detectable transcripts except for Paneth cells that expressed CD95L mRNA at high levels. In ulcerative colitis, CD95L mRNA-positive inflammatory cells were increased in number, and metaplastic Paneth cells were the only epithelial cells expressing CD95L. Paneth cells are CD95 negative. Therefore, these cells may not commit CD95-mediated autocrine suicide. By secreting soluble CD95L, however, the Paneth cells might contribute to mucosal integrity.

Base Sequence↗
PubMed1977

Paneth cells in experimental amyloidosis.

The effect of experimental amyloidosis on the morphology of the Paneth cells of the mouse was investigated by using light and fluorescence microscopy. Amyloidosis was induced by daily subcutaneous casein injections for 4 weeks. It was found that the number of secretory granules of the Paneth cells increased in the jejunum, but remained normal in the duodenum. Small morphological alterations took place in the Paneth cells during the induction of amyloidosis, and occasionally the Paneth cells were totally lost. These changes suggest that the function of the Paneth cells of the jejunum may be partly inhibited during experimental amyloidosis.

Amyloidosis↗
PubMed1980

Identification of neoplastic Paneth cells in an adenocarcinoma of the stomach using lysozyme as a marker, and electron microscopy.

A large number of cells containing large eosinophilic granules in their supranuclear cytoplasm was observed in a well differentiated adenocarcinoma of the stomach and its metastases. These cells were identified as Paneth cells by electron microscopy and by their content of lysozyme. Lysozyme-immunoreactivity was well preserved after fixation of tumor tissue in liquid formaldehyde followed by postfixation in osmium tetroxide. Immunoreactivity at immunoelectron microscopy was confined to the large osmiophilic secretory granules. We conclude that morphologically and biochemically differentiated Paneth cells occasionally occur in neoplasms of the gastrointestinal tract.

Adenocarcinoma↗
PubMed2001

Spatial distribution and histogenesis of colorectal Paneth cell metaplasia in idiopathic inflammatory bowel disease.

BACKGROUND AND AIM: Colorectal Paneth cell metaplasia (PCM) is known to be a sign of idiopathic inflammatory bowel disease (IBD), although its distribution and histogenesis are not fully understood. Objectives of this research were to investigate the spatial distribution of PCM in IBD and other forms of colitis (non-IBD), and to find stimuli causing PCM. METHODS: We studied multiple biopsy specimens from 181 patients with ulcerative colitis (UC), 159 with Crohn's disease (CD), 448 with non-IBD, and 78 normal controls. Paneth cell metaplasia frequency, at each colorectal site, was evaluated to find possible differences among diseases, phases of activity, and extents of disease. RESULTS: In non-IBD and controls, PCM was rarely (0-1.9%) seen at distal sites, but frequently (up to 48.7%) found at the ascending colon and cecum (P < 0.001). Paneth cell metaplasia frequency was significantly higher in IBD than in non-IBD patients and controls at distal sites (P < 0.001), but did not differ significantly between UC and CD, or among active, resolving, and quiescent phases. In UC, proctitis and left-sided colitis rarely displayed PCM at unaffected sites. Multiple logistic regression analysis revealed that PCM was positively associated with crypt distortion and mononuclear cell infiltration (P < 0.005), but negatively or not significantly associated with crypt atrophy, mucin depletion, acute inflammation, or phase of activity. CONCLUSIONS: Paneth cell metaplasia is a non-specific phenomenon in the proximal colon, but distal PCM, which occurs exclusively in affected mucosa, is a useful marker indicating IBD, even in the inactive phase. Regression analysis suggests that repair and regeneration may be the most potent stimuli causing PCM.

Adult↗
PubMed2001

Enhanced expression of transforming growth factor (TGF) -alpha precursor and TGF-beta1 during Paneth cell regeneration.

An intravenous injection of diphenylthiocarbazone (dithizone), a zinc chelator, induces selective killing and rapid regeneration of Paneth cells, which have a large amount of zinc in their cytoplasmic granules. We examined the expression pattern of transforming growth factor (TGF) -alpha and TGF-beta1 in this regenerative process. Messenger RNA expression of TGF-alpha and TGF-beta1 reached their peaks at 12 and 24 hr after dithizone injection, respectively. Protein expression of TGF-alpha precursor and TGF-beta1 increased to a maximum at 24 and 72 hr, respectively. Their immunoreactivities were localized in the epithelial cells in the vicinity of Paneth cells, whereas they were prominent in the upper half of the crypts in control rats. In conclusion, destruction of Paneth cells induced TGF-alpha precursor expression, followed by an increase of TGF-beta1 especially in the crypt bases. This unique expression pattern of two growth factors may be involved in rapid regeneration of Paneth cells.

Animals↗
PubMed1984

Ultrastructure of Paneth cells in germ-free rats, with special reference to the secretory granules and lysosomes.

Ultrastructure and acid phosphatase activity in Paneth cells, which are thought to play a role in regulation of the intestinal flora, were observed in control and germ-free rats (5 weeks of age, male). Examination of the germ-free rats revealed: secretory granules with coarse and a low-electron dense matrix in the duodenal, jejunal and ileal Paneth cells; numerous and larger lysosomes in ileal Paneth cells; and contact or fusion between the secretory granules and lysosomes in ileal Paneth cells. Acid phosphatase activities in Paneth cells were observed in the GERL of Novikoff (1964) and lysosomes in germ-free as well as control rats. None of the secretory granules showed any acid phosphatase activity. The fact that the lysosomes fused with the secretory granules suggests that the process of crinophagy occurred in the Paneth cells of germ-free rats.

Acid Phosphatase↗
PubMed2004

Abnormal Paneth cell granule dissolution and compromised resistance to bacterial colonization in the intestine of CF mice.

Paneth cells of intestinal crypts contribute to host defense by producing antimicrobial peptides that are packaged as granules for secretion into the crypt lumen. Here, we provide evidence using light and electron microscopy that postsecretory Paneth cell granules undergo limited dissolution and accumulate within the intestinal crypts of cystic fibrosis (CF) mice. On the basis of this finding, we evaluated bacterial colonization and expression of two major constituents of Paneth cells, i.e., alpha-defensins (cryptdins) and lysozyme, in CF murine intestine. Paneth cell granules accumulated in intestinal crypt lumens in both untreated CF mice with impending intestinal obstruction and in CF mice treated with an osmotic laxative that prevented overt clinical symptoms and mucus accretion. Ultrastructure studies indicated little change in granule morphology within mucus casts, whereas granules in laxative-treated mice appear to undergo limited dissolution. Protein extracts from CF intestine had increased levels of processed cryptdins compared with those from wild-type (WT) littermates. Nonetheless, colonization with aerobic bacteria species was not diminished in the CF intestine and oral challenge with a cryptdin-sensitive enteric pathogen, Salmonella typhimurium, resulted in greater colonization of CF compared with WT intestine. Modest downregulation of cryptdin and lysozyme mRNA in CF intestine was shown by microarray analysis, real-time quantitative PCR, and Northern blot analysis. Based on these findings, we conclude that antimicrobial peptide activity in CF mouse intestine is compromised by inadequate dissolution of Paneth cell granules within the crypt lumens.

Animals↗
PubMed2001

Modulation of mouse Paneth cell alpha-defensin secretion by mIKCa1, a Ca2+-activated, intermediate conductance potassium channel.

Paneth cells in small intestinal crypts secrete microbicidal alpha-defensins in response to bacteria and bacterial antigens (Ayabe, T., Satchell, D. P., Wilson, C. L., Parks, W. C., Selsted, M. E., and Ouellette, A. J. (2000) Nat. Immunol. 1, 113- 38). We now report that the Ca(2+)-activated K(+) channel mIKCa1 modulates mouse Paneth cell secretion. mIKCa1 cDNA clones identified in a mouse small intestinal crypt library by hybridization to human IKCa1 cDNA probes were isolated, and DNA sequence analysis showed that they were identical to mIKCa1 cDNAs isolated from erythroid cells and liver. The genomic organization was found to be conserved between mouse and human IKCa1 as shown by comparisons of the respective cDNA and genomic sequences. Reverse transcriptase-PCR experiments using nested primers amplified mIKCa1 from the lower half of bisected crypts and from single Paneth cells, but not from the upper half of bisected crypts, villus epithelium, or undifferentiated crypt epithelial cells, suggesting a lineage-specific role for mIKCa1 in mouse small bowel epithelium. The cloned mIKCa1 channel was calcium-activated and was blocked by ten structurally diverse peptide and nonpeptide inhibitors with potencies spanning 9 orders of magnitude and indistinguishable from that of the human homologue. Consistent with channel blockade, charybdotoxin, clotrimazole, and the highly selective IKCa1 inhibitors, TRAM-34 and TRAM-39, inhibited (approximately 50%) Paneth cell secretion stimulated by bacteria or bacterial lipopolysaccharide, measured both as bactericidal activity and secreted cryptdin protein, but the inactive analog, TRAM-7, did not block secretion. These results demonstrate that mIKCa1 is modulator of Paneth cell alpha-defensin secretion and disclose an involvement in mucosal defense of the intestinal epithelium against ingested bacterial pathogens.

Amino Acid Sequence↗
PubMed1990

Neoplastic Paneth cells in the experimental murine carcinoma of the small intestine.

The purpose of this study is to elucidate the participation of Paneth cells in experimentally induced adenocarcinoma of the intestine. The rats were fed with N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) dissolved in drinking water ad libitum at a concentration of 100 micrograms/ml for 28 weeks. They were sacrificed 12 weeks after the last MNNG administration. A number of tumor cells containing large eosinophilic granules in their supranuclear cytoplasm (Paneth cells) were observed in about 20% of the experimentally induced adenocarcinoma of the small intestine. The granules were stained positively with Lendrum, periodic acid-Schiff, Masson's trichrome, and Mallory's phosphotungstic acid hematoxylin. Ultrastructurally, the granules were round, osmiophilic, and relatively even in size. We compared the morphologic features of the Paneth cell-containing small intestinal adenocarcinomas (Group I) with those without Paneth cells (Group II). Group I was distinguished from Group II by its better differentiation, larger tumor size and lower incidence of calcification. Although Paneth cells are extremely rare in human gastrointestinal carcinomas, twenty percent of MNNG-induced intestinal carcinomas harbor Paneth cells. The neoplastic Paneth cells in experimental carcinomas may differentiate from uncommitted cells in the deeper portion of the crypt.

Adenocarcinoma↗
PubMed1998

Fine structural and histochemical study of equine Paneth cells.

Ultrastructure, lysozyme and glycoconjugate activity in duodenal Paneth cells were observed concurrently in the horse. Paneth cells were seen to uniformly line the base of the equine intestinal glands. The round secretory granules have centrally located electron densities with peripherally located electron lucent halos. Histochemically, the peripheral halo layer was positively stained for carbohydrates by the periodic acid-thiocarbohydrazide-silver protein-physical development (PA-TCH-SP-PD) method and the entire granules reacted positively to the WGA. The central core area reacted with anti-lysozyme. We identified a young (Type I) and an old (Type II) cell population in the same crypt, but we suggest that the observed populations are variations of the same cell type with the varied appearance due to aging of the secretory granules.

Animals↗
PubMed2004

Truncated mouse adenomatous polyposis coli reduces connexin32 content and increases matrilysin secretion from Paneth cells.

Heterozygous mutations in adenomatous polyposis coli (APC) is an early event in inheritable and sporadic colon cancer development. We recently found reduced connexin (Cx43) expression in intestinal cell lines with heterozygous Apc mutation. In this study we investigated Cx expression and the role of one mutated Apc allele in epithelia of multiple intestinal neoplasia (Min) mouse intestines by immunohistochemistry. Cx43 was not expressed in intestinal epithelia of Min and wild-type mice. Cx32 was specifically expressed in enterochromaffin cells in both mice types, and in Paneth cells of wild-type mice. In contrast, Min mice had nearly undetectable level of Cx32 in Paneth cells. Isolated small intestinal crypts from Min mice had markedly increased secretion of both lysozyme and matrilysin compared with wild-type mice. Absence of matrilysin in Min mice reduces adenoma development. Reduced Cx32 and increased matrilysin secretion from Paneth cells could be important to neoplastic development in the intestine.

Adenomatous Polyposis Coli↗
PubMed1976

The Paneth cell population of the small intestine of the rat-effects of fasting and zinc deficiency on total count and on dithizone-reactive count.

The distribution of Paneth cells in the rat small intestine was found to be approximately one per crypt in the duodenum, two to three per crypt in the jejunum and four to six per crypt in the ileum. The ileum has more Paneth cells containing dithizone-reactive zinc than the duodenum and jejunum. Zinc deficiency had no significant effect on the total Paneth cell count but no dithizone-reactive Paneth cells were found in any area of the small intestine examined in zinc-deficient animals. Fasting for 3 days had no significant effect on the Paneth cell count but after a 4-day fast there was a significant rise in the total Paneth cell count accompanied by a fall in the percentage of Paneth cells containing dithizone-reactive zinc in all areas examined.

Adult↗