Adenovirus-mediated gene transfer of interleukin-4 into pancreatic stellate cells promotes interleukin-10 expression.
Pancreatic stellate cells (PSC) are crucially involved in the development of fibrosis, a hallmark of chronic pancreatitis. Therefore, PSC represent an attractive target for the modulation of cellular functions providing the prerequisite for the establishment of novel therapeutic strategies like transfer of genetic material to the cells. Based on recent studies suggesting that the chronic course of pancreatitis is associated with immune deviation towards a Th1 cytokine profile, we have investigated the applicability of primary PSC to an adenovirus-mediated transfer of the cDNA encoding the Th2 cytokine interleukin (IL) 4 and the autocrine-acting effects of IL 4 on the cells in vitro. The transduction of primary PSC with a replication-incompetent adenovirus type 5 vector carrying the cDNA encoding rat IL- 4 resulted in a distinct expression of the cytokine on mRNA and protein level for two weeks. Similar to recombinant IL 4, effects of the endogenously synthesized cytokine were mediated by the signal transducer and activator of transcription (STAT)6. Interestingly, beside the increase of PSC proliferation, IL 4 transduction was accompanied by an up-regulation in the endogenous expression of the anti-inflammatory cytokine IL 10. In summary, our data suggest that PSC are suitable targets for gene therapy modulating cellular interactions in the pancreas.
Brock
Peter
P
Department of Medicine, Division of Gastroenterology, Medical Faculty, University of Rostock, Rostock, Germany.
Sparmann
Gisela
G
Ritter
Thomas
T
Jaster
Robert
R
Liebe
Stefan
S
Emmrich
Jörg
J
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D049109:Cell Proliferation; D002478:Cells, Cultured; D005786:Gene Expression Regulation; D018014:Gene Transfer Techniques; D016753:Interleukin-10 / Q000096:biosynthesis*; D015847:Interleukin-4 / Q000235:genetics / Q000378:metabolism*; D008297:Male; D010179:Pancreas / Q000166:cytology / Q000378:metabolism*; D051381:Rats; D011917:Rats, Inbred Lew; D011994:Recombinant Proteins / Q000378:metabolism; D050800:STAT6 Transcription Factor / Q000378:metabolism
D011994:Recombinant Proteins; D050800:STAT6 Transcription Factor; C494101:STAT6 protein, human; D016753:Interleukin-10; D015847:Interleukin-4