Distribution of Indian hedgehog and its receptors patched and smoothened in human chronic pancreatitis.
Indian hedgehog (IHH) and its receptors patched (PTC) and smoothened (SMO) belong to the hedgehog family of signaling molecules, which are essential for a variety of patterning events during mammalian tIssue development. IHH plays a role in pancreas organogenesis and differentiation, as well as in the regulation of insulin production. In the present study, the expression of IHH and its receptors was analyzed in normal human pancreatic and chronic pancreatitis (CP) tIssues using Northern blotting, immunohistochemistry and Western blotting, and was correlated with clinicopathological parameters. In addition, the effects of inhibition and stimulation of the hedgehog signaling pathway on cell growth were determined in TAKA-1 normal pancreatic ductal cells. IHH mRNA was expressed in the normal human pancreas and CP tIssues, with slightly higher expression levels in CP. Using immunohistochemistry, IHH and its receptors were localized mainly in the islet cells of the normal pancreas. In CP, IHH and its receptors were present in the cells forming tubular complexes and in the islets with a different signal pattern compared with the islets in the normal pancreas. Correlation between diabetic and non-diabetic CP patients revealed no significant difference in IHH, SMO, or PTC immunoreactivity. Inhibition of hedgehog signaling in TAKA-1 pancreatic ductal cells using cyclopamine significantly reduced their growth through cell cycle arrest, while stimulation of the IHH pathway enhanced the growth of these cells. In conclusion, IHH and its receptors are expressed in the normal human pancreas and in CP, yet with a different distribution and cellular localization. IHH signaling may be involved in the pathogenesis of CP, i.e. in the formation and proliferation of tubular complexes and in islet cell dysfunction.
Kayed
H
H
Department of General Surgery, University of Heidelberg, Heidelberg, Germany.
Kleeff
J
J
Keleg
S
S
Büchler
M W
MW
Friess
H
H
D000328:Adult; D000368:Aged; D015152:Blotting, Northern / Q000379:methods; D015153:Blotting, Western / Q000379:methods; D016022:Case-Control Studies; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D002908:Chronic Disease; D003920:Diabetes Mellitus / Q000378:metabolism*; D005260:Female; D005434:Flow Cytometry; D053823:Hedgehog Proteins; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D007515:Islets of Langerhans / Q000737:chemistry; D008297:Male; D008565:Membrane Proteins / Q000032:analysis* / Q000235:genetics; D008875:Middle Aged; D010179:Pancreas / Q000737:chemistry* / Q000166:cytology / Q000187:drug effects; D010183:Pancreatic Ducts / Q000737:chemistry; D010195:Pancreatitis / Q000378:metabolism*; D000072079:Patched Receptors; D012333:RNA, Messenger / Q000032:analysis; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled / Q000032:analysis* / Q000235:genetics; D000072086:Smoothened Receptor; D015534:Trans-Activators / Q000032:analysis* / Q000235:genetics / Q000494:pharmacology
D053823:Hedgehog Proteins; D008565:Membrane Proteins; D000072079:Patched Receptors; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; C491023:SMO protein, human; D000072086:Smoothened Receptor; D015534:Trans-Activators