Abstract
The role of pancreatic acinar cells in initiating necro-inflammatory responses during the early onset of alcoholic acute pancreatitis (AP) has not been fully evaluated. We investigated the ability of acinar cells to generate pro- and anti-inflammatory mediators, including inflammasome-associated IL-18/caspase-1, and evaluated acinar cell necrosis in an animal model of AP and human samples. Rats were fed either an ethanol-containing or control diet for 14 weeks and killed 3 or 24 h after a single lipopolysaccharide (LPS) injection. Inflammasome components and necro-inflammation were evaluated in acinar cells by immunofluorescence (IF), histology, and biochemical approaches. Alcohol exposure enhanced acinar cell-specific production of TNFα, IL-6, MCP-1 and IL-10, as early as 3 h after LPS, whereas IL-18 and caspase-1 were evident 24 h later. Alcohol enhanced LPS-induced TNFα expression, whereas blockade of LPS signaling diminished TNFα production in vitro, indicating that the response of pancreatic acinar cells to LPS is similar to that of immune cells. Similar results were observed from acinar cells in samples from patients with acute/recurrent pancreatitis. Although morphologic examination of sub-clinical AP showed no visible signs of necrosis, early loss of pancreatic HMGB1 and increased systemic levels of HMGB1 and LDH were observed, indicating that this strong systemic inflammatory response is associated with little pancreatic necrosis. These results suggest that TLR-4-positive acinar cells respond to LPS by activating the inflammasome and producing pro- and anti-inflammatory mediators during the development of mild, sub-clinical AP, and that these effects are exacerbated by alcohol injury.
Highlights
Our findings indicate that pancreatic acinar cells can produce cytokines and chemokines that are involved in the inflammatory response, including the inflammasome-associated factors IL-18 and caspase-1, which are found in the basolateral region of acinar cells
The expression profile of cytokines and chemokines, as well as the inflammasome-associated expression of IL-18 and caspase-1, clearly indicate that the inflammatory mediators released during the early response to LPS are produced exclusively by acinar cells, because few a-amylase-negative cells were positive for these factors
Alcohol-injured acinar cells increase their expression of inflammatory mediators and inflammasome-related components after endotoxemia, suggesting that the alcohol-exacerbated LPS response that initiates sub-clinical acute pancreatitis (AP) is mediated by acinar cells
Summary
NFkB is the central transcription factor for proinflammatory factors such as TNFa, IL-6, MCP-1, and IL-18, and anti-apoptotic factors such as Bcl-XL, manipulation of the NFkB pathway in acinar cell-specific transgenic mouse models has recently yielded contradictory results, suggesting caution in interpreting the role of NFkB in models of pancreatitis and in clinical settings.[11,12,13,14,15,16,17,18] The NFkB pathway is extremely complex as NFkB-induced TNFa expression is pro-inflammatory in many diseases, but can be pro-apoptotic or necrotic in pancreatitis, complicating the search for adequate therapeutic interventions for this potentially lifethreatening conditions.[19,20]. Experimental models of alcoholic pancreatitis have shown that lipopolysaccharide (LPS) exacerbates the development of alcoholic AP and that repeated exposure to LPS results in fibrogenesis and chronic pancreatitis (CP).[21,22,23,24] We recently reported that the combination of alcohol and endotoxemia attenuated the apoptotic response, and inhibited autophagy signaling promoted the early onset of AP, which supports clinical observations that episodes of acute and recurrent pancreatitis can progress to CP.[22,24] Alcoholics seem more susceptible to AP, a condition associated with an earlier onset, more frequent episodes and an increased risk of CP.[25,26,27,28]. As the inflammatory response of acinar cells to endotoxin has become clinically relevant in alcoholism, we analyzed whether acinar cells respond directly to alcohol and LPS and are able to generate the injury signals necessary to initiate necro-inflammatory responses
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