Pancreatic Stellate Cells and CX3CR1

Abstract

Objectives Numerous studies suggest important roles of the chemokine, fractalkine (CX3CL1) in acute/chronic pancreatitis, however the possible mechanisms of the effects are unclear. Pancreatic stellate cells (PSCs) can play important roles in pancreatitis, secreting inflammatory cytokines/chemokines, as well as proliferation. Therefore, we investigated CX3CL1 receptor (CX3CR1) occurrence in normal pancreas and pancreatitis (acute/chronic) tissues, and the effects of CX3CL1 on activated-PSCs. Methods CX3CR1 expression/localization in normal pancreas and pancreatitis (acute/chronic) tissues were evaluated with immunohistochemical analysis. CX3CR1 expression and effects of CX3CL1 on activated-PSCs were examined with realtime-PCR, BrdU assays and Western Blotting. Results In normal pancreas, acinar cells expressed CX3CR1 within granule-like-formations in the cytoplasm, whereas in acute/chronic pancreatitis, acinar, ductal and activated-PSCs expressed CX3CR1 on cell membranes. With activation of normal PSCs, CX3CR1 is increased. CX3CL1 activated multiple signaling cascades in PSCs. CX3CL1, did not induce inflammatory-genes expression in activated-PSCs, but induced proliferation. Conclusions CX3CR1s are expressed in normal pancreas. Expression is increased in acute/chronic pancreatitis and the CX3CR1s are activated. CX3CL1 induces proliferation of activated-PSCs without increasing release of inflammatory-mediators. These results suggest that CX3CR1 activation of PSCs could be important in their effects in pancreatitis, especially to PSCs proliferation in pancreatitis where CX3CL1 levels are elevated.

BAG3‐positive pancreatic stellate cells promote migration and invasion of pancreatic ductal adenocarcinoma

“…Quiescent PSCs have key function in regulation of extracellular matrix turnover and in maintenance of normal tissue architecture . On the contrast, activated PSCs play a central role in PDAC growth, evasion of immune surveillance, invasion, metastasis and resistance to chemotherapy . Interestingly, the current study showed that conditioned media from BAG3‐overexpression PSCs facilitate migration and invasion of PDACs, implying that BAG3 may interlink PDACs and PSCs via regulating secretion function of PSCs.…”

“…27,28 On the contrast, activated PSCs play a central role in PDAC growth, evasion of immune surveillance, invasion, metastasis and resistance to chemotherapy. [29][30][31][32] Interestingly, the current study showed that conditioned media from BAG3-overexpression PSCs facilitate migration and invasion of PDACs, implying that BAG3 may interlink and function as a RNA binding protein. 37,38 Thereby, BAG3 might also regulate some genes expression at the post-transcriptional and translational levels via interaction with target transcripts.…”

Pancreatic stellate cell: Pandora's box for pancreatic disease biology

“…Proliferation and migration of PSCs is mediated by PDGF[ 57 , 72 , 73 ] (which is expressed after TGF-β mediated activation) and endothelin-1[ 74 , 75 ]. A proinflammatory chemokine, CX3CL1 (fractalkine), reported to circulate in the serum of patients with alcoholic chronic pancreatitis, was demonstrated as an activation and proliferation factor for PSCs and PSCs were shown to express the receptor (CX3CR1) for this chemokine[ 76 , 77 ]. Interestingly, this chemokine and its receptor system was reported to regulate the insulin secretion by β-cells[ 78 ].…”

Endoscopic Pancreas Fluid Collection: Methods and Relevance for Clinical Care and Translational Science

“…Another study demonstrated neutrophil gelatinase-associated lipocalin and macrophage inhibitory cytokine 1 also discriminate between these pancreatic diseases and controls as well as differentiating subjects with PDAC with and without a history of diabetes mellitus, respectively (29). Other potentially relevant cytokines that have been investigated in animals include fractalkine (CX3CL1) and connective tissue growth factor (or CCN2) (34–37). …”