Human Transforming Growth Factor Alpha (TGF-alpha) is Digested to a Smaller (1-43), Less Biologically Active, Form in Acidic Gastric Juice

Overview

Journal Gut

Specialty Gastroenterology

Date 2002 Nov 13

PMID 12427777

Citations 3

Authors

T Marchbank

R Boulton

H Hansen

R J Playford

Affiliations

Soon will be listed here.

Abstract

Background: Transforming growth factor alpha (TGF-alpha) is a 50 amino acid peptide with potent proliferative and cytoprotective activity present in gastric mucosa and juice.

Aims: To determine the forms and biological activity of natural and recombinant TGF-alpha following incubation with acid pepsin.

Patients: Human gastric juice was obtained under basal conditions from patients taking acid suppressants and from volunteers undergoing intragastric neutralisation.

Methods: Samples were analysed using mass spectroscopy and/or high pressure liquid chromatography with radioimmunoassay. Biological activity was determined using thymidine incorporation into rat hepatocytes and an indomethacin/restraint induced gastric damage rat model.

Results: TGF-alpha(1-50) is cleaved to TGF-alpha(1-43) by acid pepsin and this is the predominant form in normal gastric juice. However, intragastric neutralisation or taking acid suppressants caused the predominant form to be TGF-alpha(1-50). TGF-alpha(1-43) had only half of the ability to maximally stimulate [(3)H]thymidine incorporation into primary rat hepatocytes (28 177 (1130) DPM/well for 2.16 nM TGF-alpha(1-43) v 63 184 (3536) DPM/well for TGF-alpha(1-50); p<0.001). A similar reduced potency was seen when used in an indomethacin induced rat gastric damage model (0.18 micro mol/kg/h of TGF-alpha(1-43) reduced ulcer area by 19% whereas TGF-alpha(1-50) reduced area by 62%; p<0.001).

Conclusions: TGF-alpha(1-50) is cleaved to the TGF-alpha(1-43) form by acid pepsin, causing 2-5-fold loss of biological activity. Such changes may have relevance to the actions of acid suppressants and the importance of this peptide in both normal and abnormal growth.

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References

Chen M, Lee A, Soll A . Mitogenic response of canine fundic epithelial cells in short-term culture to transforming growth factor alpha and insulinlike growth factor I. J Clin Invest. 1991; 87(5):1716-23. PMC: 295275. DOI: 10.1172/JCI115189. View

Tam J, Lin Y, Liu W, Wang D, Ke X, Zhang J . Mapping the receptor-recognition site of human transforming growth factor-alpha. Int J Pept Protein Res. 1991; 38(3):204-11. DOI: 10.1111/j.1399-3011.1991.tb01430.x. View

Troyer K, Luetteke N, Saxon M, Qiu T, Xian C, Lee D . Growth retardation, duodenal lesions, and aberrant ileum architecture in triple null mice lacking EGF, amphiregulin, and TGF-alpha. Gastroenterology. 2001; 121(1):68-78. DOI: 10.1053/gast.2001.25478. View

Itoh M, Imai S, Joh T, Yokoyama Y, Yasue N, Iwai A . Effect of epidermal growth factor in combination with sucralfate or omeprazole on the healing of chronic gastric ulcers in the rat. J Clin Gastroenterol. 1990; 12 Suppl 1:S187-91. DOI: 10.1097/00004836-199001001-00030. View

Rutten M, Dempsey P, Solomon T, Coffey Jr R . TGF-alpha is a potent mitogen for primary cultures of guinea pig gastric mucous epithelial cells. Am J Physiol. 1993; 265(2 Pt 1):G361-9. DOI: 10.1152/ajpgi.1993.265.2.G361. View

Richman R, Claus T, Pilkis S, Friedman D . Hormonal stimulation of DNA synthesis in primary cultures of adult rat hepatocytes. Proc Natl Acad Sci U S A. 1976; 73(10):3589-93. PMC: 431163. DOI: 10.1073/pnas.73.10.3589. View

Playford R, Marchbank T, Calnan D, Calam J, Royston P, BATTEN J . Epidermal growth factor is digested to smaller, less active forms in acidic gastric juice. Gastroenterology. 1995; 108(1):92-101. DOI: 10.1016/0016-5085(95)90012-8. View

Selden C, Hodgson H . Further characterisation of 'hepatotropin', a high molecular weight hepatotrophic factor in rat serum. J Hepatol. 1989; 9(2):167-76. DOI: 10.1016/0168-8278(89)90047-0. View

Konturek S, Brzozowski T, Majka J, Dembinski A, Slomiany A, Slomiany B . Transforming growth factor alpha and epidermal growth factor in protection and healing of gastric mucosal injury. Scand J Gastroenterol. 1992; 27(8):649-55. DOI: 10.3109/00365529209000134. View

10.

Levi S, Shaw-Smith C . Non-steroidal anti-inflammatory drugs: how do they damage the gut?. Br J Rheumatol. 1994; 33(7):605-12. DOI: 10.1093/rheumatology/33.7.605. View

11.

Playford R, Hanby A, Gschmeissner S, Peiffer L, Wright N, McGarrity T . The epidermal growth factor receptor (EGF-R) is present on the basolateral, but not the apical, surface of enterocytes in the human gastrointestinal tract. Gut. 1996; 39(2):262-6. PMC: 1383309. DOI: 10.1136/gut.39.2.262. View

12.

Playford R, Woodman A, Clark P, Watanapa P, Vesey D, Deprez P . Effect of luminal growth factor preservation on intestinal growth. Lancet. 1993; 341(8849):843-8. DOI: 10.1016/0140-6736(93)93057-8. View

13.

Kataoka H, Joh T, Kasugai K, Kato T, Moriyama A . Mitogenic properties of human gastric juice. Dig Dis Sci. 1997; 42(8):1747-54. DOI: 10.1023/a:1018877918894. View

14.

Konturek J, Konturek S, Stachura J, Domschke W . Helicobacter pylori-positive peptic ulcer patients do not adapt to aspirin. Aliment Pharmacol Ther. 1998; 12(9):857-64. DOI: 10.1046/j.1365-2036.1998.00385.x. View

15.

Rao R, Thomas D, Pepperl S, Porreca F . Salivary epidermal growth factor plays a role in protection of ileal mucosal integrity. Dig Dis Sci. 1997; 42(10):2175-81. DOI: 10.1023/a:1018855525989. View

16.

Di Marco E, PIERCE J, Aaronson S, Di Fiore P . Mechanisms by which EGF receptor and TGF alpha contribute to malignant transformation. Nat Immun Cell Growth Regul. 1990; 9(3):209-21. View

17.

Mann G, Fowler K, Gabriel A, Nice E, Williams R, Dunn A . Mice with a null mutation of the TGF alpha gene have abnormal skin architecture, wavy hair, and curly whiskers and often develop corneal inflammation. Cell. 1993; 73(2):249-61. DOI: 10.1016/0092-8674(93)90227-h. View

18.

Derynck R . Transforming growth factor-alpha: structure and biological activities. J Cell Biochem. 1986; 32(4):293-304. DOI: 10.1002/jcb.240320406. View

19.

Cartlidge S, Elder J . Transforming growth factor alpha and epidermal growth factor levels in normal human gastrointestinal mucosa. Br J Cancer. 1989; 60(5):657-60. PMC: 2247287. DOI: 10.1038/bjc.1989.334. View

20.

Scheving L, Shiurba R, Nguyen T, Gray G . Epidermal growth factor receptor of the intestinal enterocyte. Localization to laterobasal but not brush border membrane. J Biol Chem. 1989; 264(3):1735-41. View