Pancreatitis-associated protein: From a lectin to an anti-inflammatory cytokine

Closa, Daniel; Motoo, Yoshiharu; Iovanna, Juan

doi:10.3748/wjg.v13.i2.170

Cited by 56 publications

(45 citation statements)

References 41 publications

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“…The family of regenerating proteins, including Reg1 and Pap, is highly induced during AP and is involved in tissue repair and anti-inflammatory functions (37,38). Administration of IL-12 plus IL-18 induced high levels of mRNA expression of Reg1 and Pap in the pancreas of WT mice, whereas only a small, nonsignificant increase was observed in ob/ob mice.…”

Section: Discussionmentioning

confidence: 99%

Interleukin-18, together with interleukin-12, induces severe acute pancreatitis in obese but not in nonobese leptin-deficient mice

Sennello¹,

Fayad²,

Pini³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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Obesity is associated with increased severity of acute pancreatitis (AP). The cytokines IL-18 and IL-12 are elevated in patients with AP, and IL-18 levels are high in obesity. We aimed to develop a pathologically relevant model to study obesity-associated severe AP. Lean WT and obese leptin-deficient ob/ob mice received two injections of IL-12 plus IL-18. Survival, pancreatic inflammation, and biochemical markers of AP were measured. Dosing with IL-12 plus IL-18 induced 100% lethality in ob/ob mice; no lethality was observed in WT mice. Disruption of pancreatic exocrine tissue and acinar cell death as well as serum amylase and lipase levels were significantly higher in ob/ob than in WT mice. Edematous AP developed in WT mice, whereas obese ob/ob mice developed necrotizing AP. Adipose tissue necrosis and saponification were present in cytokine-injected ob/ob but not in WT mice. Severe hypocalcemia and elevated acute-phase response developed in ob/ob mice. The cytokine combination induced high levels of regenerating protein 1 and pancreatitis-associated protein expression in the pancreas of WT but not of ob/ob mice. To differentiate the contribution of obesity to that of leptin deficiency, mice received short-and long-term leptin replacement therapy. Shortterm leptin reconstitution in the absence of major weight loss did not protect ob/ob mice, whereas leptin deficiency in the absence of obesity resulted in a significant reduction in the severity of the pancreatitis. In conclusion, we developed a pathologically relevant model of AP in which obesity per se is associated with increased severity.cytokines ͉ inflammation ͉ obesity ͉ pancreas A cute pancreatitis (AP) is an inflammatory disorder that ranges from interstitial edema to confluent necrosis and hemorrhage. In severe cases, progress to circulatory shock, acute lung injury, renal failure, and eventual death may occur (1). Despite some controversy, numerous studies have demonstrated that obesity is associated with increased risk of the severe form of AP and with development of life-threatening complications (2-8). However, the mechanism by which increased adiposity worsens AP remains unknown.Leptin, a protein mainly produced by adipocytes, is a critical regulator of appetite (9). Leptin exerts important regulatory effects on inflammation (10). In the context of AP, the role of leptin remains controversial. In patients with AP, a correlation between serum leptin and disease severity has been reported by some investigators but not by others (11,12). Although in animal models administration of leptin decreases AP severity (13-16), more severe disease is present in leptin-deficient ob/ob and leptin receptordeficient db/db mice as well as leptin-receptor mutant fa/fa rats (17, 18). However, the differential effect of obesity versus leptin deficiency has not been fully investigated.IL-12 and IL-18 are two proinflammatory cytokines that drive the Th1 cell response, characterized by high levels of IFN-␥ (19). Both cytokines are mainly produced by monocytes/macrophages....

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Section: Discussionmentioning

confidence: 99%

Interleukin-18, together with interleukin-12, induces severe acute pancreatitis in obese but not in nonobese leptin-deficient mice

Sennello¹,

Fayad²,

Pini³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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“…RegIIIβ, initially found in the pancreatic juice of rats with acute pancreatitis (19), is a 16-kDa secretory protein structurally related to the C-type lectins (27). The anti-inflammatory function of RegIIIβ in acute pancreatitis was evidenced by various experimental approaches (28 -30).…”

Section: Discussionmentioning

confidence: 99%

Over-Expression of Pancreatic Pituitary Adenylate Cyclase–Activating Polypeptide (PACAP) Aggravates Cerulein-Induced Acute Pancreatitis in Mice

Hamagami¹,

Sakurai²,

Shintani³

et al. 2009

J Pharmacol Sci

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Abstract. Development of human chronic pancreatitis is associated with intrapancreatic accumulation of pituitary adenylate cyclase-activating polypeptide (PACAP) accompanied with an altered inflammatory response (Michalski et al., Am J Physiol Gastrointest Liver Physiol. 2008;294:G50-G57). To investigate the role of pancreatic PACAP in the development of acute pancreatitis, we employed transgenic mice over-expressing PACAP in pancreatic β-cells (PACAP-Tg). In comparison to wild-type mice, PACAP-Tg mice exhibited more severe pathophysiological signs of the cerulein-induced pancreatitis at 12 h, as evidenced by higher serum amylase and lipase levels accompanied by the exacerbation of pancreatic edema, necrosis, and inflammation. Cerulein treatment increased mRNA expression of several proinflammatory cytokines (TNFα, IL-1β, and IL-6) at 12 h with similar magnitude both in wild-type and PACAPTg mice. In addition, the mRNA and protein levels of regenerating gene III β (RegIIIβ), a key factor in the pancreatic response to acute pancreatitis, were up-regulated at 24 h in wild-type mice upon cerulein administration, whereas they were attenuated in PACAP-Tg mice. These data indicate that over-expressed PACAP in pancreas enhances the cerulein-induced inflammatory response of both acinar cells, leading to aggravated acute pancreatitis, which was accompanied by a down-regulation of RegIIIβ, an anti-inflammatory factor.

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“…Serum PSP was transiently increased after stress such as anesthesia in animals without pancreatic injury (82) and critical diseased in the ICU patients (77). Pro-and anti-inflammatory cytokines might induce expression of PSP/Reg/PAP family (11, 29,71,72,83). Pancreatic stellate cells (PSC) play a central role in fibrogenesis associated with acute and chronic pancreatitis.…”

Section: Anti-inflammatory Activity and Prognostic Indicatormentioning

confidence: 99%

Pancreatic Stone Protein/Regenerating Protein Family in Pancreatic and Gastrointestinal Diseases

Jin

Hayakawa

et al. 2011

Intern. Med.

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Pancreatic stone protein (PSP; reported in 1979), pancreatitis-associated protein (PAP; 1984) and regenerating protein (Reg I;1988) were discovered independently in the fields of the exocrine (pancreatitis) and endocrine (diabetes) pancreas. Subsequent analysis revealed that PSP and Reg I are identical and PAP belongs to the same protein family. PSP/Reg I and PAP share a selective and specific trypsin cleavage site and result in insoluble fibrils (PTP, PATP). Search for a functional role of PSP had led to the idea that it might serve as an inhibitor in pancreatic stone formation and PSP was renamed lithostathine. Inhibitory effects of lithostathine in stone formation have been questioned. Evidence so far obtained can support a lithogenic role rather than a lithostatic role of PSP. PAP and its isoforms have been investigated mainly regarding responses to inflammation and stress. Reg I and its isoforms have been examined on regeneration, growth and mitogenesis in gastrointestinal neoplastic diseases as well as diabetes. Evidence obtained can be applied in the prediction of prognosis and therapy for inflammatory and neoplastic diseases.

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Pancreatitis-associated protein: From a lectin to an anti-inflammatory cytokine

Cited by 56 publications

References 41 publications

Interleukin-18, together with interleukin-12, induces severe acute pancreatitis in obese but not in nonobese leptin-deficient mice

Interleukin-18, together with interleukin-12, induces severe acute pancreatitis in obese but not in nonobese leptin-deficient mice

Over-Expression of Pancreatic Pituitary Adenylate Cyclase–Activating Polypeptide (PACAP) Aggravates Cerulein-Induced Acute Pancreatitis in Mice

Pancreatic Stone Protein/Regenerating Protein Family in Pancreatic and Gastrointestinal Diseases

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