Patients with Helicobacter pylori-associated gastritis have an increased release of gastrin. The mechanisms by which H. pylori affects the endocrine cells are unclear. We have used primary cultures containing canine antral G cells to examine the effects of human blood mononuclear cells, purified monocytes and lymphocytes, recombinant cytokines, and NH4Cl on gastrin release. Mononuclear cells and purified monocytes in direct contact with G cells stimulated gastrin release dose dependently. Separating mononuclear cells from G cells by Transwell filters with 0.4-micron pore size still produced a significant increase of gastrin release. Three human recombinant cytokines, interferon-gamma, tumor necrosis factor-alpha, and interleukin-2, but not interleukin-6 and interleukin-1 beta, each produced dose-dependent increases of gastrin stimulation. NH4Cl did not stimulate gastrin release. We conclude that mononuclear cells and purified monocytes prepared from human blood, as well as several cytokines, stimulate gastrin release from antral G cells. These factors may play an important role in the pathogenesis of H. pylori-associated hypergastrinemia.

Studying primary cultures of replicating canine oxyntic mucosal cells, we found evidence for modulation of cell growth by endogenous factors. [3H]thymidine incorporation into DNA was rapid with cells cultured in medium free of serum or added growth factors, and growth rates of these cultures were markedly dependent on plating density, indicating mitogenic control by soluble endogenous growth factors. Data indicated that endogenous transforming growth factor-alpha (TGF-alpha) exerted mitogenic control under the following conditions. 1) TGF-alpha was detected in the cultured cells by radioimmunoassay and immunohistochemistry. 2) TGF-alpha-like immunoreactivity and receptor reactivity were present in the medium in concentrations sufficient to exert mitogenic control. 3) Receptors for TGF-alpha and epidermal growth factor (EGF) were present in the cultures. 4) Immunoabsorption by a TGF-alpha-specific antisera reduced [3H]thymidine incorporation. TGF-alpha was localized to parietal cells by immunohistochemistry and cell separation. In contrast, combined [3H]thymidine autoradiography and immunohistochemistry with anti-TGF-alpha did not detect TGF-alpha in dividing cells. We conclude that parietal cell TGF-alpha exerts paracrine control of mucosal cell growth in vitro, and we speculate that this is an important paracrine mechanism in vivo.

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Evidence in vivo indicates that endogenous and exogenous prostaglandins can alter gastrin secretion. We have used primary cultures containing canine antral G-cells to study the cellular actions of prostaglandins on gastrin secretion, comparing the effects of prostaglandin E2 (PGE2) and its synthetic analogue enprostil. Enprostil (10(-10)-10(-6) M) inhibited gastrin secretion in response to bombesin, carbachol, and forskolin, the latter a receptor-independent activator of adenylate cyclase. This inhibition by enprostil was reversed by treatment with pertussis toxin (200 ng/ml, 8 h). However, enprostil did not inhibit the postreceptor stimuli 8-bromoadenosine 3',5'-cyclic monophosphate (10(-3) M), calcium ionophore A-23187 (10(-7) M), or 4 beta-phorbol 12-myristate 13-acetate (10(-8) M). In contrast, whereas PGE2 inhibited forskolin-stimulated gastrin release, PGE2 did not inhibit the response to carbachol or bombesin in control cultures. However, in pertussis toxin-treated cultures, PGE2 inhibition was reversed and, in contrast, the responses to bombesin, carbachol, and possibly forskolin were augmented. Indomethacin at a dose of 10(-5) M did not alter basal or bombesin-stimulated gastrin secretion. However, the somatostatin antibody CURE-S6 enhanced the response to forskolin and enhanced inhibition by PGE2, suggesting that endogenous somatostatin produced an inhibitory tone in these cultures and excluding the possibility that PGE2 acted via release of endogenous somatostatin. Our data suggest that in cultured antral cells gastrin release is regulated by inhibitory and stimulatory prostaglandin mechanisms.(ABSTRACT TRUNCATED AT 250 WORDS)

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