Fibroblasts stimulate acinar cell proliferation through IGF-I during regeneration from acute pancreatitis

Pancreatic regeneration after caerulein-induced pancreatitis is characteriz ed by transient fibroblast proliferation followed by replication of acinar cells. The mechanisms that coordinate regeneration are incompletely underst ood. In this study, we examine the role of insulin-like growth factor I (IG F-I). Acute edematous pancreatitis was induced in rats by 12 h caerulein in fusion. Pancreatic IGF-I mRNA levels increased over 50-fold during regenera tion, reaching a maximum at day 2. Immunohistochemically, IGF-I was localiz ed to fibroblasts within the areas of interstitial tissue. IGF-I mRNA was d emonstrated in primary cultures of pancreatic fibroblasts but not in cultur ed pancreatic acinar cells. However, with the use of Western blotting acina r cells did express IGF-I receptors. IGF-I stimulated 5-bromo-2'-deoxyuridi ne uptake and increased numbers of acinar cells in a dose-dependent manner. Stimulation was half maximal at 1.1 nM and completely inhibited by an IGF- I antagonist and by IGF binding protein-3 (IGFBP-3). Possible paracrine reg ulation was confirmed by stimulation of acinar cell proliferation with fibr oblast-conditioned medium, which was partially inhibited by IGF-I antagonis t or by IGFBP-3. We conclude that acinar cell proliferation during late reg eneration from pancreatitis is mediated at least in part by paracrine relea se of IGF-I from fibroblasts.