Endogenous interleukin-10 modulates fibrosis and regeneration in experimental chronic pancreatitis

Abstract

Interleukin (IL)-10, a potent anti-inflammatory cytokine, limits the severity of acute pancreatitis and downregulates transforming growth factor (TGF)-beta release by inflammatory cells on stimulation. Proinflammatory mediators, reactive oxygen species, and TGF-beta can activate pancreatic stellate cells and their synthesis of collagen I and III. This study evaluates the role of endogenous IL-10 in the modulation of the regeneration phase following acute pancreatitis and in the development of pancreatic fibrosis. IL-10 knockout (KO) mice and their C57BL/6 controls were submitted to repeated courses (3/wk, during 6 wk, followed by 1 wk of recovery) of cerulein-induced acute pancreatitis. TGF-beta(1) release was measured on plasma, and its pancreatic expression was assessed by quantitative RT-PCR and immunohistochemistry. Intrapancreatic IL-10 gene expression was assessed by semiquantitative RT-PCR, and intrapancreatic collagen content was assessed by picrosirius staining. Activated stellate cells were detected by immunohistochemistry. S phase intrapancreatic cells were marked using tritiated thymidine labeling. After repeated acute pancreatitis, IL-10 KO mice had more severe histological lesions and fibrosis (intrapancreatic collagen content) than controls. TGF-beta(1) plasma levels, intrapancreatic transcription, and expression by ductal and interstitial cells, as well as the number of activated stellate cells, were significantly higher. IL-10 KO mice disclosed significantly fewer acinar cells in S phase, whereas the opposite was observed for pseudotubular cells. Endogenous IL-10 controls the regeneration phase and limits the severity of fibrosis and glandular atrophy induced by repeated episodes of acute pancreatitis in mice.

Interleukin-10 deficiency aggravates kidney inflammation and fibrosis in the unilateral ureteral obstruction mouse model

“…Studies in other organs, including lung, heart, pancreas and liver, also showed IL-10 could suppress inflammatory response and thereby inhibit matrix remodeling and fibrosis process, even if fibrosis had developed. [31][32][33][34][35][36][37] Here, we provide direct evidence supporting the role of IL-10 in renal fibrosis by demonstrating that knockout of IL-10 leads to more severe inflammatory response and renal injury and fibrosis in the UUO model. In addition, we found that knockout of IL-10 enhanced activation of TGF-b/Smad3 and NF-kB pathways at days 7 and 14 after UUO, which are known to have central roles in the initiation and progression of renal inflammation and fibrosis through inducing a wide array of genes encoding pro-inflammatory cytokines, adhesion molecules, and chemokines in human and experimental models of kidney diseases.…”

“…9 The role of IL-10 in fibrosis has been also reported in other organs such as lung, heart and pancreas fibrosis. [10][11][12] The underlying mechanism of antifibrotic effects of IL-10 remains unclear, but it has been suggested that IL-10 can suppress extracellular matrix synthesis and inhibit key inflammatory pathways such as NF-kB. [13][14][15] In the context of kidney, IL-10 has been reported to effectively suppress the progression of acute and chronic renal damage in vivo.…”

Immortalization of pancreatic stellate cells as an in vitro model of pancreatic fibrosis: deactivation is induced by matrigel and N-acetylcysteine

“…65,66 In conclusion, we were able to establish an immortal cell line from human pancreas, which is phenotypically and functionally indistinguishable from primary activated PSC with respect to the expression of stellate cell markers (vimentin, aSMA and GFAP) and their response to TGFb1 and PDGF treatment. Importantly, we were able to demonstrate that besides soluble factors, the matrix surrounding PSC plays a pivotal role in the maintenance of the activation process of PSC, as cultivation of activated PSC on a reconstituted basement membrane plus treatment with NAC was able to deactivate the cells, thus pointing to the possibility of an antifibrosis therapy in chronic pancreatitis.…”

Disordered Pancreatic Inflammatory Responses and Inhibition of Fibrosis in CD39-Null Mice

“…Severity of cerulein induced pancreatitis was graded by a semi-quantitative scoring system as previously described. 19 Briefly, pancreatic sections, were investigated regarding parameters such as tissue architecture changes (graded as: 0=absent, 1=rare, 2=minimal (<10%), 3=moderate (<50%) and 4=major (>50%) of the total parenchyma affected), fibrosis (0 = absent, 2=only within areas, and 4=diffuse), glandular atrophy (0=absent, 1=minimal, 2=moderate, 3=major) and presence of pseudotubular complexes (0=absent, 1=minimal, 2=moderate, 3=major). These parameters were graded and a total score was calculated for each pancreatic specimen.…”