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Transgenic expression of pancreatic secretory trypsin inhibitor-1 rescues SPINK3-deficient mice and restores a normal pancreatic phenotype.

Publication ,  Journal Article
Romac, JM-J; Ohmuraya, M; Bittner, C; Majeed, MF; Vigna, SR; Que, J; Fee, BE; Wartmann, T; Yamamura, K-I; Liddle, RA
Published in: Am J Physiol Gastrointest Liver Physiol
April 2010

Endogenous trypsin inhibitors are synthesized, stored, and secreted by pancreatic acinar cells. It is believed that they play a protective role in the pancreas by inhibiting trypsin within the cell should trypsinogen become prematurely activated. Rodent trypsin inhibitors are highly homologous to human serine protease inhibitor Kazal-type 1 (SPINK1). The mouse has one pancreatic trypsin inhibitor known as SPINK3, and the rat has two trypsin inhibitors commonly known as pancreatic secretory trypsin inhibitors I and II (PSTI-I and -II). Rat PSTI-I is a 61-amino acid protein that shares 65% sequence identity with mouse SPINK3. It was recently demonstrated that mice with genetic deletion of the Spink3 gene (Spink3(-/-)) do not survive beyond 15 days and lack normal pancreata because of pancreatic autophagy. We have shown that targeted transgenic expression of the rat Psti1 gene to acinar cells in mice [TgN(Psti1)] protects mice against caerulein-induced pancreatitis. To determine whether the autophagic phenotype and lethality in Spink3(-/-) mice were due to lack of pancreatic trypsin inhibitor, we conducted breeding studies with Spink3(+/-) heterozygous mice and TgN(Psti1) mice. We observed that, whereas Spink3(+/+), Spink3(+/-), and Spink3(-/-)/TgN(Psti1) mice had similar survival rates, no Spink3(-/-) mice survived longer than 1 wk. The level of expression of SPINK3 protein in acini was reduced in heterozygote mice compared with wild-type mice. Furthermore, endogenous trypsin inhibitor capacity was reduced in the pancreas of heterozygote mice compared with wild-type or knockout mice rescued with the rat Psti1 gene. Surprisingly, the lesser amount of SPINK3 present in the pancreata of heterozygote mice did not predispose animals to increased susceptibility to caerulein-induced acute pancreatitis. We propose that a threshold level of expression is sufficient to protect against pancreatitis.

Duke Scholars

Published In

Am J Physiol Gastrointest Liver Physiol

DOI

EISSN

1522-1547

Publication Date

April 2010

Volume

298

Issue

4

Start / End Page

G518 / G524

Location

United States

Related Subject Headings

  • Trypsin Inhibitor, Kazal Pancreatic
  • Trypsin
  • Transgenes
  • Survival Rate
  • Sequence Homology, Amino Acid
  • Rats
  • Prostatic Secretory Proteins
  • Pancreatitis
  • Pancreas, Exocrine
  • Pancreas
 

Citation

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Romac, J.-J., Ohmuraya, M., Bittner, C., Majeed, M. F., Vigna, S. R., Que, J., … Liddle, R. A. (2010). Transgenic expression of pancreatic secretory trypsin inhibitor-1 rescues SPINK3-deficient mice and restores a normal pancreatic phenotype. Am J Physiol Gastrointest Liver Physiol, 298(4), G518–G524. https://doi.org/10.1152/ajpgi.00431.2009
Romac, Joelle M-J, Masaki Ohmuraya, Cathy Bittner, M Faraz Majeed, Steven R. Vigna, Jianwen Que, Brian E. Fee, Thomas Wartmann, Ken-ichi Yamamura, and Rodger A. Liddle. “Transgenic expression of pancreatic secretory trypsin inhibitor-1 rescues SPINK3-deficient mice and restores a normal pancreatic phenotype.Am J Physiol Gastrointest Liver Physiol 298, no. 4 (April 2010): G518–24. https://doi.org/10.1152/ajpgi.00431.2009.
Romac JM-J, Ohmuraya M, Bittner C, Majeed MF, Vigna SR, Que J, et al. Transgenic expression of pancreatic secretory trypsin inhibitor-1 rescues SPINK3-deficient mice and restores a normal pancreatic phenotype. Am J Physiol Gastrointest Liver Physiol. 2010 Apr;298(4):G518–24.
Romac, Joelle M. J., et al. “Transgenic expression of pancreatic secretory trypsin inhibitor-1 rescues SPINK3-deficient mice and restores a normal pancreatic phenotype.Am J Physiol Gastrointest Liver Physiol, vol. 298, no. 4, Apr. 2010, pp. G518–24. Pubmed, doi:10.1152/ajpgi.00431.2009.
Romac JM-J, Ohmuraya M, Bittner C, Majeed MF, Vigna SR, Que J, Fee BE, Wartmann T, Yamamura K-I, Liddle RA. Transgenic expression of pancreatic secretory trypsin inhibitor-1 rescues SPINK3-deficient mice and restores a normal pancreatic phenotype. Am J Physiol Gastrointest Liver Physiol. 2010 Apr;298(4):G518–G524.

Published In

Am J Physiol Gastrointest Liver Physiol

DOI

EISSN

1522-1547

Publication Date

April 2010

Volume

298

Issue

4

Start / End Page

G518 / G524

Location

United States

Related Subject Headings

  • Trypsin Inhibitor, Kazal Pancreatic
  • Trypsin
  • Transgenes
  • Survival Rate
  • Sequence Homology, Amino Acid
  • Rats
  • Prostatic Secretory Proteins
  • Pancreatitis
  • Pancreas, Exocrine
  • Pancreas