Unsaturated but not saturated fatty acids induce transcriptional regulation of CCL2 in pancreatic acini. A potential role in acute pancreatitis

Abstract

Fatty acids (FAs) are massively released from peripancreatic fat during acute pancreatitis (AP) and they were shown, as a whole, to induce inflammatory response in pancreatic acini. We investigated the mechanisms triggered by the major saturated FAs (SFAs) and unsaturated FAs (UFAs) in modulating the expression of chemokine (C–C motif) ligand 2 (CCL2) in acinar cells. Pancreatic acini of control rats were treated with palmitic acid (PA) or stearic acid (SA), as SFAs, or oleic acid (OA) or linoleic acid (LA), as UFAs. By using specific inhibitors, the involvement of MAPKs (JNK, ERK, p38), JAK, NF-κB and STAT3 pathways was assessed. The role of PPARγ pathway was studied by using 15-Deoxy-Δ(12,14)-prostaglandin J(2) (15d-PGJ2). CCL2 mRNA was analyzed by qRT-PCR. By western blot, phosphorylated forms of MAPKs and JAK as well as IκB-α were analyzed in cytoplasm and p65-NF-κB and phospho-STAT3 in nucleus. No effect was found in PA- or SA-treated acini. Conversely, in response to OA or LA, MAPKs and JAK acted as upstream signals, driving the CCL2 up-regulation transcriptionally mediated by the synergic action of NF-κB and STAT3. By blocking the activation of NF-κB and STAT3, 15d-PGJ2 totally inhibited the OA- and LA-induced CCL2 overexpression. We conclude that the most common UFAs, but not the SFAs, represented in peripancreatic fat and released during AP, are capable of up-regulating the acinar expression of CCL2, which depends on the activation of MAPK/JAK-mediated NF-κB and STAT3 pathways. By targeting both transcription factors, PPARγ agonists could be indicated as potential therapy in AP.