© 2014 APMIS. Published by John Wiley & Sons Ltd. DOI 10.1111/apm.12280

APMIS 122: 1171–1177

Expression of group XIIA phospholipase A2 in human digestive organs HEIKKI PEURAVUORI, SINIKKA KOLLANUS and TIMO J. NEVALAINEN Department of Pathology, University of Turku, Turku, Finland

Peuravuori H, Kollanus S, Nevalainen TJ. Expression of group XIIA phospholipase A2 in human digestive organs. APMIS 2014; 122: 1171–1177. Cellular distribution of group XIIA phospholipase A2 (GXIIA PLA2) was studied in human digestive organs by immunohistochemistry. GXIIA PLA2 protein was detected in epithelial cells of normal gastrointestinal tract, gallbladder and pancreatic acinar cells. The GXIIA PLA2 protein was evenly distributed in the cytoplasm in contrast to secretory granular distribution of GIB PLA2 and GIIA PLA2 in pancreatic acinar cells and small intestinal Paneth cells respectively. Epithelial cells of intestinal glands in Crohn’s disease and ulcerative colitis expressed abundant GXIIA PLA2, whereas inflammatory cells were devoid of the enzyme protein. Tumour cells in colonic adenomas and carcinomas and pancreatic ductogenic carcinomas expressed GXIIA PLA2 protein at varying intensity levels. The putative functions of GXIIA PLA2 remain to be investigated and its role in healthy and diseased digestive organs can only be speculated on at present. Key words: Group XIIA phospholipase A2; gastrointestinal tract; pancreas; gallbladder. Heikki Peuravuori, Department of Pathology, University of Turku, Kiinamyllynkatu 10, FI-20520 Turku, Finland. e-mail: heipeu@utu.fi

The superfamily phospholipase A2 (PLA2) comprises numerous enzymes and enzyme-like proteins in organisms ranging from bacteria to vertebrates. PLA2s are classified into three broad categories of calcium-dependent secreted PLA2s (sPLA2) and cytosolic PLA2s and calcium-independent cytosolic PLA2s. There are 18 distinct groups of sPLA2s synthesized by many different cell types and secreted in various body fluids. Secreted PLA2s participate in important physiological and pathological functions, such as digestion of dietary phospholipids, inflammatory reaction, antimicrobial defence and venom toxicity (1–4). Group XIIA PLA2 (GXIIA PLA2) and a catalytically inactive GXII PLA2-like protein (GXIIB PLA2) were cloned from human (5, 6). Recently, GXIIA PLA2s was identified in bacteria, fungi and metazoans, but GXIIB PLA2s in vertebrates only (7). Functional characterization of GXIIA PLA2 revealed that its catalytic activity is relatively low in comparison with other sPLA2s (5). The tissue distributions of GXIIA PLA2 and GXIIB PLA2 Received 14 December 2013. Accepted 10 March 2014

transcripts have been studied by Northern blotting and PCR (5, 6) and GXIIA PLA2 protein has been detected by immunohistochemistry in various human tissues (8; http://www.proteinatlas.org/ENSG 00000123739/normal), but the cellular localization and function of GXIIA PLA2 in diseased digestive organs are largely unknown. The purpose of the current investigation was to study by immunohistochemistry the sites of expression of GXIIA PLA2 protein in normal, inflamed and neoplastic tissues of human digestive organs. MATERIALS AND METHODS Materials Ninety-two formalin-fixed and paraffin-embedded tissue samples from adult male and female patients were retrieved from the surgical biopsy archive of the Department of Pathology of the University of Turku. Demographic data are summarized in Table 1. Cylinders 3 mm in diameter were taken from paraffin blocks containing histologically normal and pathological tissues guided by eosin-haematoxylin-stained sections representing the whole block face and re-embedded in paraffin for tissue microarray (9).

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Table 1. Expression of GXIIA phospholipase A2 protein in histological specimens from digestive organs of 92 subjects (44 males and 48 females). The intensity of the immunoreaction was graded visually to negative, weak, moderate or strong. The figures indicate the number of subjects in each immunoreaction intensity category. M, male; F, female Tissue, histological diagnosis Number, gender and age Negative Weak Moderate Strong range of subjects staining staining staining staining Oesophagus, normal 1 M (75) 1 Oesophagus, squamous cell carcinoma 9 M (48–73), 8 F (52–74) 17 Oesophagus, adenocarcinoma 1 M (68), 1 F (62) 1 1 Stomach, corpus, normal 1 M (62) 1 Stomach, carcinoma, intestinal type 4 M (57–81), 5 F (32–94) 2 6 1 Stomach, carcinoma, diffusion type 3 M (57–71), 4 F (45–71) 7 Small intestine, normal 2 M (58–61), 3 F (49–86) 2 3 Small intestine, Crohn’s disease 2 M (25–26), 2 F (32–40) 1 3 Large intestine, normal 3 F (36–79) 3 Large intestine, ulcerative colitis 2 M (37–63), 3 F (13–23) 3 1 1 Large intestine, adenoma 2 M (45–62), 5 F (43–78) 7 Large intestine, carcinoma 2 M (43–68), 4 F (71–85) 5 1 Gall bladder 2 F (68–77) 1 1 Pancreas, normal 2 M (64–68) 1 1 Pancreas carcinoma 13 M (34–74), 8 F (44–78) 9 12

Immunohistochemistry For immunohistochemistry, 3-lm thick sections were cut from paraffin-embedded tissue blocks on Superfrost+ slides. Antigen retrieval was performed by heating the sections in a microwave oven in 10 mmol/L sodium citrate, pH 9 two times for 7 min. Endogenous peroxidase activity was blocked with 3% hydrogen peroxide. The specimens were stained with a monoclonal antihuman GXIIA PLA2 antibody (Abnova Corporation, clone 1D11, Fig 1, at a dilution 1:500), an IgG fraction of a polyclonal rabbit anti-human recombinant GIIA PLA2 antibody (1:3000) (10) or a monoclonal anti-human GIB PLA2 antibody (1:500) (11) using a Lab Vision automated slide stainer 480 (Thermo Fisher Scientific, Fremont, CA, USA). Power Vision plus poly-HRP kit (Immunovision Technologies, Vision Biosystems, Norwell, MA, USA) was used to detect the primary immunoreaction. The cell types displaying positive staining were identified and the intensity of the immunoreaction was graded visually as negative, weak, moderate or strong.

RESULTS GXIIA PLA2 protein was localized by immunohistochemistry in tissue samples from the digestive organs

Fig. 1. The 99 amino acid peptide used as antigen to raise the monoclonal anti-GXIIA PLA2 antibody 1D11 (Abnova) is underlined in the human GXIIA PLA2 sequence (UniProt Q9BZM1). The catalytic histidine (H) and aspartic acid (D) residues are highlighted in red and the 22 amino acid signal peptide is in italics.

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of 92 subjects (44 males and 48 females, Table 1). In sections with normal histological structure, there was positive immunoreaction in the epithelial cells of gastric corpus and antrum, duodenum, ileum, colon and gallbladder and in pancreatic acinar cells, whereas oesophageal squamous epithelial cells gave negative immunoreaction. All 17 cases of oesophageal squamous carcinomas investigated were negative, whereas one adenocarcinoma was weakly positive and another adenocarcinoma negative for GXIIA PLA2 immunoreaction (Table 1). Cells of non-neoplastic gastric glands expressed GXIIA PLA2 protein. There was strong immunoreaction for GXIIA PLA2 in the cytoplasm of chief (zymogenic) cells in the glands of corpus mucosa. Mucous neck cells were weakly immunoreactive and parietal (oxyntic) cells were unstained (Fig. 2A). Gland cells in inflamed pyloric mucosa were stained to varying intensity for GXIIA PLA2. There was no immunoreaction in mononuclear inflammatory cells in the lamina propria. The immunoreaction in intestinal type gastric carcinomas ranged from weak to moderate, but the tumour cells in diffuse type carcinomas were negative for GXIIA PLA2 (Table 1). In intestinal type gastric carcinoma, the immunoreaction was localized in the apical cytoplasm of cells around the lumen of neoplastic glands (Fig. 2B). The epithelium lining the villi of normal duodenal mucosa showed strong GXIIA PLA2 immunoreaction, whereas Brunner’s glands and the villous lamina propria were unstained. GXIIA PLA2 was localized in the cytoplasm of epithelial cells including columnar (absorptive), goblet and Paneth cells in the entire small intestine (Fig. 2C). The staining pattern was different when adjacent sections of © 2014 APMIS. Published by John Wiley & Sons Ltd

EXPRESSION OF GROUP XIIA PHOSPHOLIPASE A2

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Fig. 2. (A) Normal gastric corpus. Strong immunoreaction for PLA2 in chief (zymogenic) cells in gastric glands. Parietal (oxyntic) cells are unstained. Anti-GXIIA PLA2 antibody. (B) Intestinal type gastric carcinoma. GXIIA PLA2 immunoreaction is localized in the apical cytoplasm of cells around the lumen of neoplastic glands in intestinal type gastric carcinoma. Anti-GXIIA PLA2 antibody. (C) Duodenum. Immunoreaction for GXIIA PLA2 in the cytoplasm of the epithelial cells lining the villi of duodenal mucosa. Mucin-secreting mucosal glands, submucosal Brunner’s glands and mononuclear cells in the lamina propria are unstained. Anti-GXIIA PLA2 antibody. (D) Duodenum. Paneth cells at the bottom of the crypts of Lieberk€ uhn contain GIIA PLA2, whereas epithelial cells lining the villi, as well as the cells of mucin-secreting glands, are devoid of immunoreaction. Anti-GIIA PLA2 antibody. (E) Colon. Uulcerative colitis. There is strong immunoreaction for GXIIA PLA2 in the apical cytoplasm of columnar epithelial cells in the deformed glands of heavily inflamed colonic mucosa. Anti-GXIIA PLA2 antibody. (F) Carcinoma of colon. There is strong immunoreaction for GXIIA PLA2 in the apical cytoplasm of neoplastic gland cells in colonic carcinoma. Inflammatory cells and the tumour stroma are devoid of immunoreactive material. Anti-GXIIA PLA2 antibody. (G) Gallbladder. Immunoreaction for GXIIA PLA2 in the cytoplasm of the columnar epithelial cells of the mucosa. Anti-GXIIA PLA2 antibody. (H) Normal pancreas. Strong immunoreaction for GXIIA PLA2 evenly distributed in acinar cell cytoplasm of normal pancreas. There is weak immunoreaction in the cells of the islet of Langerhans Anti-GXIIA PLA2 antibody.

© 2014 APMIS. Published by John Wiley & Sons Ltd

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small intestinal mucosa were reacted with the antiGIIA PLA2 antibody. Only Paneth cells at the bottom of the crypts of Lieberk€ uhn contained GIIA PLA2, whereas epithelial cells lining the villi, as well as Brunner’s gland cells were devoid of immunoreaction (Fig. 2D). Furthermore, no GIB PLA2-containing cells were observed in the gastrointestinal tract. In Crohn’s disease, there was moderate-tostrong immunoreaction for GXIIA PLA2 in the epithelial cells of the inflamed mucosa (Table 1). In normal colon, the immunoreaction for GXIIA PLA2 was localized in the cytoplasm of columnar epithelial cells and in the thin rim of cytoplasm of mucus-filled goblet cells. In ulcerative colitis, the gland cells displayed immunostaining ranging from weak to strong, whereas inflammatory cells were devoid of immunoreactive material (Table 1; Fig. 2E). The cytoplasm of the epithelial cells of adenomas of colon (both tubular and villous types) contained GXIIA PLA2 (Table 1). Neoplastic gland cells in carcinomas of colon expressed GXIIA PLA2 protein ranging from weak to strong immunoreaction (Table 1). GXIIA PLA2 immunoreaction was localized the apical cytoplasm of neoplastic gland cells, whereas inflammatory cells and the tumour stroma were devoid of immunoreactive material (Fig. 2F). Columnar epithelial cells in normal gallbladder mucosa displayed even cytoplasmic immunostaining for GXIIA PLA2 (Table 1; Fig. 2G). In normal pancreas, there was evenly distributed immunoreaction for GXIIA PLA2 in the cytoplasm of acinar cells. In addition, the cells of the islet of Langerhans displayed weak immunoreaction (Fig. 2H). The immunoreaction for pancreatic GIB PLA2 was characteristically concentrated in the secretory (zymogen) granules in the vicinity of the acinar lumen (Fig. 3A). All 21 pancreatic carcinomas studied were ductogenic, and approximately half of them displayed immunostaining and half

A

were negative for GXIIA PLA2 immunoreaction (Table 1). The immunoreaction was localized in the cytoplasm of the cells forming neoplastic glands (Fig. 3B).

DISCUSSION GXIIA PLA2 was cloned from human (5) and the gene was localized in 4q25. The 21 kD protein precursor comprises 189 amino acid residues including a signal peptide of 22 amino acids, and the mature protein chain of 167 amino acids contains 14 cysteine residues, but the exact positions of disulphide bonds have not been determined. Later, a catalytically inactive human GXII PLA2-like protein (GXIIB PLA2) was cloned (6) and the gene localized in 10q22.1. The mature GXIIB PLA2 protein contains 176 amino acid residues including 14 cysteines. The mRNA of GXIIA PLA2 is strongly expressed in human heart and skeletal muscle, kidney and pancreas, whereas GXIIB PLA2 is mainly expressed in liver, small intestine and kidney (5, 6). GXIIA PLA2 protein was localized by immunohistochemistry in a large number of human tissues including normal pancreas and gastrointestinal mucosa (8). In the current study, we identified cell types expressing GXIIA PLA2 protein in normal and diseased human digestive organs including the gastrointestinal tract, gallbladder and pancreas by immunostaining histological sections of surgical specimens with a monoclonal anti-human GXIIA PLA2 antibody. We observed even distribution of GXIIA PLA2 in the epithelial cell cytoplasm of gastrointestinal mucosa, gallbladder and pancreatic acinar cells. Cell types specialized in protein secretion, such as gastric chief cells, pancreatic acinar cells and Paneth cells contain GXIIA PLA2 in their cytoplasm, and it can

B

Fig. 3. (A) Normal pancreas. Secretory (zymogen) granules in the acinar cell cytoplasm show strong immunoreaction for GIB PLA2. Duct cells (arrow) are devoid of immunoreactive material. Anti-GIB PLA2 antibody. (B) Pancreatic carcinoma. Immunoreaction for GXIIA PLA2 in cuboidal cells lining the neoplastic glands of pancreatic ductogenic carcinoma. AntiGXIIA PLA2 antibody.

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be speculated that the enzyme may be involved in protein synthesis and/or secretion in these cells. However, the cellular distribution of the specific secretory products in both pancreatic acinar cells and Paneth cells were distinctly different from the distribution of GXIIA PLA2. In pancreatic acinar cells, immunostaining with an antibody specific for GIB PLA2 decorated especially zymogen granules, whereas GXIIA PLA2 immunoreaction was evenly distributed in the cytoplasm. Similarly, in small intestinal mucosa, GIIA PLA2-specific antibody labelled Paneth cells only, whereas GXIIA PLA2 was localized in all epithelial cell types of the gut inner lining. GXIIA PLA2 belongs to secreted PLA2s (1) and may be secreted from the epithelial/gland cells together with their respective specific secretory proteins, such as pepsin from gastric chief cells, GIB PLA2 from pancreatic acinar cells (12) and GIIA PLA2 from Paneth cells (13). However, GXIIA PLA2 remains to be identified in these secretory products. GXIIA PLA2 was strongly expressed in intestinal epithelial cells in inflammatory bowel disease including Crohn’s disease and ulcerative colitis. The expression pattern was highly similar to that of GIIA PLA2 (14, 15). However, the enzyme is not expressed in the abundant inflammatory cell infiltrates in the affected tissues, which confirms an earlier observation that GXIIA PLA2 is not expressed in circulating human neutrophils in contrast to GV PLA2 and GX PLA2 (16). The concentration of GXIIA PLA2 protein in serum is not elevated in severe inflammatory diseases such as acute pancreatitis and sepsis in contrast to the concentrations of GIB PLA2 in acute pancreatitis and GIIA PLA2 in sepsis (17). GIIA PLA2 is an acute phase protein, and its concentration in serum is highly elevated in severe inflammatory diseases including inflammatory bowel disease (18). In the current study, we observed expression of GXIIA PLA2 protein in the neoplastic gland cells of both adenomas and carcinomas of the colon. In colonic carcinoma, the immunoreaction was localized in the apical cytoplasm around the lumen of neoplastic glands, which localization may be an indication of secretory activity. GXIIA PLA2 and GIIA PLA2 are expressed at high levels in both normal colon and colonic adenocarcinoma tissues as measured by quantitative PCR (19). GIIA PLA2 has been proposed as a tumour suppressor gene in mice (20), but such a role for the enzyme in human has been refuted (21). The role of GXIIA PLA2 in the neoplastic process remains to be investigated. We observed expression of GXIIA PLA2 protein in the cytoplasm of columnar epithelial cells lining

© 2014 APMIS. Published by John Wiley & Sons Ltd

the gallbladder lumen. Expression of GXIIA PLA2 seems to be a common occurrence in various epithelia (8; http://www.proteinatlas.org/ENSG00000 123739/normal), but the role of the enzyme in epithelial cells is unknown. Pancreatic acinar cells synthesize and secrete digestive enzymes, such as amylase, trypsin, elastase and phospholipase A2 into the duodenal lumen. Pancreatic GIB PLA2 is involved in the hydrolysis of dietary phosphatidylcholine (lecithin), and the enzyme protein has been visualized by immunohistochemistry in acinar cell secretory (zymogen) granules at both light and electron microscopical levels (12, 22). In the current study, we confirmed this localization for GIB PLA2 in normal pancreas. Furthermore, we demonstrated a different distribution pattern for GXIIA PLA2 in pancreatic acinar cells: the enzyme protein is strongly expressed and evenly distributed in the acinar cell cytoplasm, which confirms earlier immunohistochemical observations for GXIIA PLA2 (8). The acinar cell cytoplasm is packed with organelles specialized in protein syntheses and secretion including the rough surfaced endoplasmic reticulum and Golgi apparatus (22). It can be speculated that GXIIA PLA2 may be involved in the pancreatic exocrine secretory process, but the putative mechanism remains to be studied. Only weak immunostaining was observed in the cells of the islets of Langerhans. In the current study, duct cells in normal pancreas were devoid of GXIIA PLA2-immunoreactive material, and there was relatively weak positive staining only in cancer cells forming neoplastic ducts in pancreatic ductogenic carcinomas. At present, the mechanism involved in biological functions of GXIIA PLA2 are poorly characterized. The catalytic activity of GXIIA PLA2 is relatively low in comparison with the activity of other sPLA2s, and GXIIB PLA2 is devoid of catalytic activity. GXIIA sPLA2 had only weak effects on the release of arachidonic acid and production of prostaglandins (23). Therefore, it is feasible to postulate that metabolic effects of GXII PLA2s may be mediated by largely unknown non-catalytic mechanisms (5, 6). GXIIA PLA2 signalling is involved in the embryonic development of frog through crosstalk with the transforming growth factor beta pathways. GXIIA PLA2 induces in frog ectoderm ectopic olfactory structures by blocking bone morphogenetic protein signalling. The effect seems to be independent on the PLA2 hydrolytic activity (24). The antibacterial properties of secreted PLA2s have been established both in vitro and in vivo. The rank order of the antibacterial potency in vitro against the Gram-positive bacterium Listeria

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monocytogenes for human sPLA2s is GIIA > GX > GV > GXIIA > GIIE > GIB, GIIF and the potency correlates well with the hydrolytic effect on bacterial membranes (25). Transgenic mice over expressing human GIIA PLA2 are resistant against the Gram-positive Staphylococcus aureus infection (26). Interestingly, GXIIA PLA2 was found to be the only human sPLA2 effective against Gramnegative bacteria such as Escherichia coli (25) and Helicobacter pylori (27). However, in serum samples from patients suffering from severe sepsis, the level of GXIIA PLA2 is not elevated in contrast to that of GIIA PLA2 (17). This observation indicates that GXIIA PLA2 may exert its bactericidal action locally while GIIA PLA2 is delivered systematically to combat infection. In summary, our current investigation demonstrated expression of GXIIA PLA2 protein in epithelial cells of normal gastrointestinal tract, gallbladder and pancreatic acinar cells. The GXIIA PLA2 protein was evenly distributed in the cytoplasm in contrast to secretory granular distribution of GIB PLA2 and GIIA PLA2 in pancreatic acinar cells and small intestinal Paneth cells respectively. Epithelial cells in deformed intestinal glands in Crohn’s disease and ulcerative colitis expressed abundant GXIIA PLA2, whereas inflammatory cells in the lesions were devoid of the enzyme protein. Tumour cells in colonic adenomas and carcinomas and pancreatic ductogenic carcinomas expressed GXIIA PLA2 protein at varying intensity levels. The putative functions of GXIIA PLA2 in healthy and diseased digestive organs remain to be investigated.

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16. This study was supported by the EVO Research Fund of Turku University Hospital.

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Expression of group XIIA phospholipase A2 in human digestive organs.

Cellular distribution of group XIIA phospholipase A2 (GXIIA PLA2) was studied in human digestive organs by immunohistochemistry. GXIIA PLA2 protein wa...
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