Potential role of CXCL10 in the induction of cell injury and mitochondrial dysfunction

Abstract

Chemokines have been known to play a critical role in pathogenesis of chronic pancreatitis and acinar cell death. However, the role played by one of the CXC chemokines: CXCL10 in regulation of acinar cell death has remained unexplored. Hence, this study was designed to assess the role of CXCL10 promoting apoptosis in ex vivo cultured acinar cells. Primary human pancreatic acinar cell cultures were established and exposed to varying doses of CXCL10 for different time intervals. Apoptotic induction was evaluated by both qualitative as well as quantitative analyses. Various mediators of apoptosis were also studied by Western blotting, membrane potential (Psim) and ATP depletion in acinar cells. Analysis of apoptosis via DNA ladder and cell death detection - ELISA demonstrated that CXCL10 induced 3.9-fold apoptosis when administrated at an optimal dose of 0.1 mug of recombinant CXCL10 for 8 h. Quantitative analysis using FACS and dual staining by PI-annexin showed increased apoptosis (48.98 and 53.78% respectively). The involvement of upstream apoptotic regulators like pJNK, p38 and Bax was established on the basis of their increased expression of CXCL10. The change of Psim by 50% was observed in the presence of CXCL10 in treated acinar cells along with enhanced expression of Cytochrome C, apaf-1 and caspase 9/3 activation. In addition, ATP depletion was also noticed in CXCL10 stimulated acinar cells. CXCL10 induces cell death in human cultured pancreatic cells leading to apoptosis and DNA fragmentation via CXCR3 signalling. These signalling mechanisms may play an important role in parenchymal cell loss and injury in pancreatitis.

Activation of p38-MAPK by CXCL4/CXCR3 axis contributes to p53-dependent intestinal apoptosis initiated by 5-fluorouracil

“…23 CXCR3 is coupled to a G-protein signaling pathway with its downstream protein p38-MAPK. [23][24][25][26] It has been reported that CXCL10 can trigger apoptosis in several normal cellular models, such as acinar cells, 27 neurons, 28 microvascular endothelial cells, 29 and recently blood T lymphocytes. 26 However, the apoptosis pathway of CXCR3 is not yet identified.…”

Proapoptotic effects of the chemokine, CXCL 10 are mediated by the noncognate receptor TLR4 in hepatocytes

“…In the current study, we could functionally link these two observations and show that an increase of apoptotic cells within livers of HCV‐infected patients is strongly correlated with an increased mRNA expression of CXCL10. These findings, together with the knowledge of the involvement of CXCL10 in epithelial,16 pancreatic,15 and β‐cell14 injury, motivated our interest to further understand the role of CXCL10 in liver cell apoptosis.…”

“…One possible explanation is that CXCL10 might operate through a noncognate receptor and thereby mediate biological effects independent of CXCR3. Indeed, CXCL10 has been implicated in non‐chemokine‐receptor‐mediated apoptotic effects in cell culture 14‐16. However, whether these effects are also true for liver cells and whether they also operate in vivo have not yet been investigated.…”

GROβ and its downstream effector EGR1 regulate cisplatin-induced apoptosis in WHCO1 cells

“…they affect cells by activating surface receptors, which are seven-transmembranedomain g-protein-coupled receptor (5). evidence suggest that members of this group are correlated with inflammatory reaction (6), injure recovery (7), cell proliferation (8,9), apoptosis (10) and one even involved the regulation of chemotherapeutic agent-induced apoptosis (11,12). cXcl12 increases resistance of small-cell lung cancer cells to chemotherapy by activation its receptor cXcr4 (13).…”