1. Introduction

Dysregulation of multiple signaling pathways in the pancreas is proposed to be involved the initiation of pancreatitis. Genetic manipulation in experimental animals has been used to understand the critical roles of these pathways during the pathogenesis of pancreatitis. In general, the genetic approaches that specifically target these specific molecules are superior to pharmacological methods. Additionally, genetic modification of the initiator genes observed in human pancreatitis can help create clinically relevant animal models. These models will be valuable for studying the mechanisms of pancreatitis and testing preclinical therapeutic and preventive interventions.  In this review, we will focus on the impact of trypsin, NF-kB, ER stress, Ras, autophagy, Cox-2 and several others on pancreatitis. We will also discuss efforts to create animal models for human hereditary pancreatitis, cystic fibrosis, and autoimmune pancreatitis.

2. Animal Models Targeting Trypsinogen Activation

Trypsin and Pancreatitis

The exocrine pancreas synthesizes digestive enzymes to facilitate digestion. More than a century ago, Chiari (21) proposed that acute pancreatitis (AP) was an autodigestive disease. During the past two decades, researchers discovered that trypsinogen is prematurely activated in various animal models of pancreatitis and human pancreatitis (13, 39, 68, 72, 137). Because trypsin is capable of degrading proteins and initiating other zymogen activation cascades, premature activation of trypsinogen in pancreatic acinar cells is considered a key initiator of this disease. This notion is strongly supported by the observation that gain-of-function cationic trypsinogen (PRSS1) mutations and loss-of-function mutations of the potent pancreatic protease inhibitor Kazal type 1 (SPINK1) are associated with hereditary pancreatitis (HP) (8, 14, 110, 129, 132, 133, 139, 140). The mechanisms of trypsinogen activation have been extensively studied (45, 100, 109, 127). However, the roles of intracellular trypsin have only recently been directly examined. In transgenic mouse models, expression of active trypsin or mutant PRSS1 caused pancreatitis, and the expression of the trypsin inhibitor SPINK1 ameliorated experimental pancreatitis (8, 37, 87, 106).  Genetic deletion of trypsinogen 7, the most prominent trypsinogen in mice, blunted trypsinogen activation and caused a 50% reduction in acinar necrosis following caerulein challenges (25).

Models with Direct Trypsinogen Activation

Because pharmacological inhibitors have nonspecific effects, and the stimuli used to induce pancreatitis activate multiple signaling pathways in addition to activating trypsinogen (48), the direct effects of intracellular trypsin activity cannot be examined using these approaches. However, a recent study reported the development of a mutant trypsinogen that could be activated intracellularly by the endogenous protease PACE (paired basic amino acid cleaving enzyme) (61) (Fig. 1A). This new construct (PACE-trypsinogen) allowed for the first time direct examination of the effects of intracellular trypsin on pancreatic acinar cells. In in vitro studies, this PACE-trypsinogen was expressed by means of adenoviral vector in the secretory pathway and was activated within acinar cells. Expression of PACE-trypsinogen induced the apoptosis of pancreatic acinar cells. Cell death was blocked by the trypsin inhibitor pefabloc, but it was not completely blocked by the pancaspase inhibitor benzyloxycarbonyl-VAD, indicating that caspase-independent pathways were also involved. However, intracellular trypsin had no significant effect on the activity of the proinflammatory transcription factor Nuclear Factor kappa B (NF-κB). In contrast, extracellular trypsin caused cell damage and dramatically increased NF-κB activity. These data support that the effects of active trypsin on pancreatic acinar cells are determined by its localization (61). For in vivo studies, a new mouse model was developed with this construct. These mice were engineered to conditionally express an endogenously activated trypsinogen within pancreatic acinar cells after cre mediated recombination (37) (Fig. 1B). The acinar specificity was achieved by crossing these mice with mice harboring pancreatic elastase I promoter-driven CreERT, a tamoxifen-inducible cre (63) (Fig. 2A).  Commonly used pancreatic specific cre mice were summarized in Fig. 2B. Interestingly, initiation of AP was observed with high (homozygous) but not low (heterozygous) expression levels of PACE-trypsinogen. Rapid caspase-3 activation and apoptosis with delayed necrosis was observed, and lost acinar cells were replaced with abundant fatty tissue and limited fibrosis. These findings indicated that intra-acinar activation of trypsinogen is sufficient to initiate AP. This novel model will provide a powerful tool for improving our understanding of the basic mechanisms that occur during the initiation of pancreatitis (37).

Fig 1. Expression of a trypsinogen that can be activated intracellularly. A. WT trypsinogen is normally activated in duodenum by enteropeptidase (top). A mutant trypsinogen was developed by an insertion of amino acid sequence RTKR immediate before the active trypsin. RTKR sequence can be recolonized and cleave by PACE . B. In a conditional transgenic mouse line, PACE-trypsinogen expression was blocked by a loxp-GFP-stop-loxP cassette until Cre medicated recombination (37, 61).

Fig 2. Commonly used cell specific Cre mouse lines for pancreatic research. A. For inducible pancreatic acinar specific gene targeting, a tamoxifen-inducible Cre (CreERT) was introduced to a Bacterial Artificial Chromosome containing the pancreatic elastase I gene. The full length promoter of elastase I gave high efficient and specific CreERT expression in acinar cells. B. pdx1 and p48 (Ptf1a) are transcription factors expressed early in pancreatic multipotent progenitor cells (MPC). Cre driven by these promoters will be active in acinar, ductal and endocrine cells. Pancreatic elastase I promoter is pancreatic acinar cells specific. Although P48 and Mist1 are activated early in MPC, in adults they are expressed only in acinar cells. Therefore, using tamoxifen inducible CreERT system in adult, these gene promoters will only induce recombination in pancreatic acinar cells. Similarly, Pdx1 promoter is active only in endocrine cells in adult pancreas. Ngn3 drives the differentiation of endocrine islet. Cre expression driven by this gene promoter will be all pancreatic endocrine lineages. Insulin promoter is specific to beta cells. For pancreatic duct cells, CK19 and Sox9 promoters can be used. However, these genes are also expressed in many other organs.

A Model with SPINK Inactivation

SPINK1 (Serine Protease Inhibitor Kazal-type 1), also known as pancreatic secretory trypsin inhibitor (PSTI), was originally identified as a trypsin inhibitor in 1948 by Kazal et al. (65) SPINK1 is synthesized in the acinar cells of the pancreas and binds to trypsin to prevent further activation of pancreatic enzymes. Thus, a lack of SPINK1 may result in the premature conversion of trypsinogen into active trypsin in acinar cells, leading to autodigestion of the exocrine pancreas by activated proteases. The detailed functions and roles of SPINK1in pancreatic diseases have been reviewed previously (80, 95). Since Witt et al first showed that mutations in the SPINK1 gene were associated with chronic pancreatitis in 2000, (139) there have been many reports on the association between mutations in SPINK1 genes and patients with pancreatitis (10, 70, 97).

In mice, SPINK3 (Serine Protease Inhibitor Kazal type 3) is the homolog of human SPINK1. Upregulation of SPINK 3 provides a protective mechanism in caerulein-induced pancreatitis (90), and knockdown of  SPINK3  (Spink3^−/− mice) enhanced trypsin activity  in pancreatic acinar cells (93). The pancreata of Spink3^−/− mice develop usually up to 15.5 days after fertilization; however, autophagic degeneration of acinar cells, but not ductal or islet cells, begins after 16.5 days. Rapid onset of cell death occurs in the pancreas and duodenum within a few days after birth and results in death by 14.5 days after birth. There is limited inflammatory cell infiltration and no signs of apoptosis. At 7.5 days after birth, residual ductlike cells in the tubular complexes strongly express pancreatic duodenal homeodomain-containing protein 1, a marker of pancreatic stem cells, without any sign of acinar cell regeneration. These findings indicate that the progressive disappearance of acinar cells in Spink3^−/− mice was due to autophagic cell death and impaired regeneration, suggesting that SPINK3 maintains the integrity and regeneration of acinar cells (94). Although SPINK3 is also expressed in the kidney, lung, and a small proportion of cells in the gastrointestinal tract and liver (111), pancreas-specific transgenic expression of SPINK rescues SPINK3^-/- mice and restores a normal pancreatic phenotypes, supporting the critical role of SPINK3 in pancreatic homeostasis (87, 105).

Hereditary Pancreatitis-Related Models

Hereditary pancreatitis (HP) is a rare form of pancreatitis (118). The first family with HP was described by Comfort and Steinberg in 1952 (23). Using genetic linkage studies, the HP locus was independently narrowed to the long arm of chromosome 7 by Le Bodic, Whitcomb, and Pandya in 1996 (71, 98, 134).  Shortly after, Whitcomb et al (133) identified an Arg-His substitution at residue 117 of the cationic trypsinogen gene (PRSS1) in HP through mutational analysis. It was originally named R117H based on the chymotrypsin numbering system and was renamed R122H following the recommendations for gene mutation nomenclature (7, 20). Subsequently, a number of gain-of-function PRSS1 mutations were identified. The most common ones were R122H, A16V, and N29I (88). Clinically, HP is characterized by recurrent AP with an unusual early onset of the disease (5–23 years) and the development of chronic pancreatitis. Importantly, the cumulative risk of pancreatic cancer after the onset of symptoms is 44% at 70 years after the onset of the disease in HP patients. The calculated standardized incidence ratio of pancreatic cancer from the European registry of hereditary pancreatitis and pancreatic cancer (EUROPAC) cohort after correction for age, history of smoking, nationality, and surgical intervention was 67 (130).

Efforts have been made by several groups to generate an animal model mimicking the mutations harbored in HP patients with limited success. In one model, human PRSS1 mutant R122H transgenic mice were generated under using a 213-bp fragment of the rat elastase promoter/enhancer.  PRSS1 was expressed in low amounts in zymogen granules. No spontaneous development of pancreatitis was observed. However, serum pancreatic lipase levels or activity was higher in these animals after induction of pancreatitis compared to controls. Repeated caerulein insults resulted in a slightly more severe pancreatitis. This rather small difference in comparison to controls could be caused by the low expression of the transgene in the mouse pancreas (114).

Another transgenic mouse was generated in which the expression of the mouse PRSS1 mutant R122H (R122H_mPRSS1) was expressed using a rat elastase promoter (8). Acinar cell damage was detectable by 7 weeks of age with increasing inflammatory infiltrates at 12 weeks.  Fibrosis was evident in 24-week-old animals. The ultimate penetrance of this phenotype reached 40% after 1 year of age. The inflammatory phenotype varied in both extent and severity among the animals. It is surprising that the rapid response of the transgenic animals to caerulein injection was indistinguishable from that of the WT. In contrast, 1 week after injection the inflammatory phenotype in the WT animals largely resolved, while the R122H_mPRSS1 transgenic animals displayed extensive collagen deposition in the periacinar and interlobular areas, indicating a chronic inflammatory response. This is the first genetic model of chronic pancreatitis in which a genetic alteration resulted in a predicted phenotype. Unfortunately, there have been no follow-up studies published since 2006. Therefore, this model might be “lost” during breeding, probably due to unstable gene expression from the small elastase promoter.

In another recent study, Athwal et al developed a transgenic mouse model system using WT human PRSS1 and two HP-associated mutants (R122H and N29I) using a rat elastase promoter (9). The transgenic animals revealed pathological changes similar to that of chronic pancreatitis particularly in aging (> 9 months) animals. These changes occurred spontaneously in up to 10% of the animals that expressed the transgenes. When a supra-physiological dose (50 μg/kg) of caerulein was administered to the WT and PRSS1 transgenic strains, no differences in pancreatic response were observed. However, when these animals were treated with a lower dose of caerulein (20 μg/kg), the transgenic animals from each of the three transgenic strains displayed more severe pancreatitis than WT animals. The transgenic expression of PRSS1 promoted apoptotic rather than necrotic cell death. It is intriguing that no differences in phenotype were observed among these transgenic strains and that the supra-physiological dose of caerulein did not cause more severe pancreatitis in the transgenic mice compared to the WT mice.

3. Animal Models Induced by Modulating NF-κB Activity

Introduction of Nuclear Factor Kappa B (NF-κB)

The NF-κB transcription factor family is expressed in almost all cell types and tissues, and specific NF-κB binding sites are present in the promoters/enhancers of a large number of genes. These genes regulate inflammation, immunity, cell proliferation, differentiation, and survival (28). NF-κB consists of five proteins, p65 (RelA), RelB, c-Rel, p105/p50 (NF-κB1), and p100/52 (NF-κB2) that associate with each other to form distinct transcriptionally active homo- and hetero- dimeric complexes.  Among these, p65, RelB, and c-Rel contain c-terminal transactivation domains. p50 and p52 are generated by processing of the precursor molecules p105 and p100, respectively. The p50/65 heterodimer represents the most abundant form of Rel dimers and is expressed in almost all cell types.  However, not all combinations of Rel dimers are transcriptionally active: DNA-bound p50 and p52 homo- and hetero-dimers have been found to repress κB-dependent transcription. In most unstimulated cells, NF-κB dimers are retained in an inactive form in the cytosol through their interaction with IκB proteins. Degradation of these inhibitors upon their phosphorylation by the IκB kinase (IKK) complex leads to nuclear translocation of NF-κB and induction of the transcription of target genes (53, 54, 86, 115).

The canonical IKKs, IKKα and IKKβ, form a complex with the regulatory adaptor protein NF-κB essential modulator (NEMO; also known as IKKγ). IKKα and IKKβ are Ser/Thr kinases that phosphorylate the NF-κB inhibitor IκB proteins, resulting in their poly-ubiquitination and subsequent proteasomal degradation. This allows NF-κB to translocate to the nucleus and bind to specific DNA elements. Despite extensive sequence similarity, IKKα and IKKβ have largely distinct functions due to their different substrate specificities and modes of regulation. IKKβ (and IKKγ) are essential for rapid NF-κB activation by proinflammatory signaling cascades, such as those triggered by tumor necrosis factor alpha (TNFα) or lipopolysaccharide (LPS). In contrast, IKKα participates in the activation of a specific form of NF-κB in response to a subset of TNF family members and may also serve to attenuate IKKβ-driven NF-κB activation (46). Based on sequence similarities with IKKα and IKKβ, two IKK-related kinases, TANK binding kinase 1 (TBK1) and IKKɛ (also known as IKK-inducible or IKK-i), were discovered. IKKɛ and TBK1 are known as non-canonical IKKs. These protein kinases are important for the activation of interferon response factors 3 and 7. NF-κB is activated in most inflammatory diseases including animal models of AP (41, 108). Moreover, IKKs are also involved in kinase and NF-κB-independent activities (46, 92, 116, 128).

Activation of IKK2 (IKKB) Induced Pancreatitis

To specifically address the roles of NF-κB in pancreatitis, the active form of NF-κB subunit can be expressed in the pancreas.  IKK contains a canonical MAP kinase kinase activation loop motif in which phosphorylation of both serine residues is necessary for activation. Mutation of both the serine residues to glutamate residues mimics the effect of phospho-serine and generates highly active kinase activity (26, 83). An early attempt to conditionally overexpress the constitutively active mutant of IKK2 in the pancreas used a tetracycline-inducible system. To achieve transgene expression in the pancreas, tetO-IKK2-EE (EE denotes serine to glutamate mutations) animals were crossed with CMV-reverse tetracycline-responsive transactivator (rtTA) mice (66). In these double transgenic animals, doxycycline treatment induced expression of IKK2-EE in pancreatic acinar cells, resulting in moderate activation of the IKK complex. IKK2 expression in the pancreas had a mosaic pattern, and the activation level of the NF-κB cascade induced by IKK2 was considerably lower compared with that observed after supramaximal caerulein stimulation, but it still led to the formation of the leucocyte infiltrates observed after 4 weeks of doxycycline stimulation. The infiltrates were mainly composed of B lymphocytes and macrophages. However, only minor damage to pancreatic tissue was observed, indicating that a moderate level of activation is not sufficient to induce pancreatic damage in mice (4).

The influence of expression and thus activation level of NF-κB on the development of AP was confirmed by a second study from the same group of investigators published a few months later. In the new transgene system, transgenic mice expressing the rtTA gene under the control of a rat elastase promoter were generated to mediate acinar cell-specific expression of IKK2 alleles. Expression of dominant-negative IKK2 ameliorated caerulein-induced pancreatitis but did not affect trypsinogen activation. Expression of constitutively active IKK2 was sufficient to induce AP, including increased edema, cellular infiltrates, necrosis, serum lipase levels, and pancreatic fibrosis (11). These phenotypes were likely caused by higher expression levels from the tandem (tetO)₇ Promoter (50).

Activation of the IKK2/NF-κB signaling pathway causing AP is further confirmed by transgenic mice that encode the NF-κB p65 subunit or constitutively active IKK2 in the pancreatic acinar cells (57). Transgenic expression of p65 led to compensatory expression of the inhibitory subunit IΚB-α. Therefore, there is no increased NF-κB activity or clear phenotype. However, p65 transgenic mice had higher levels of NF-κB activity in acinar cells and greater levels of inflammation in pancreatic tissue upon caerulein challenge. In contrast, pancreas-specific expression of active IKK2 directly increased the activity of NF-κB in acinar cells and induced pancreatitis. Prolonged activity of IKK2 resulted in the activation of stellate cells, loss of acinar cells, and initiation of fibrosis, which are the characteristics of chronic pancreatitis. Co-expression of IKK2 and p65 further increased the expression levels of inflammatory mediators and the severity of pancreatitis (57). In addition, this pathway also orchestrated oncogenic Ras-induced inflammation and tumorigenesis, which will be further discussed below (24).

Overall, these findings indicate that NF-κB activity increased the severity of pancreatic inflammation, and strategies to inactivate NF-κB may be used to treat patients with acute or chronic pancreatitis. However, selective truncation of the p65 gene (Fig 3), which leads to the reduction the NF-κB activity, in pancreatic exocrine cells surprisingly led to both severe injury of the acinar cells and systemic adverse events (6). This is because the expression and induction of the protective pancreas-specific acute phase protein pancreatitis-associated protein 1 (PAP1) depends on RelA/p65. Lentiviral gene transfer of PAP1 cDNA reduced the severity of pancreatitis in mice with selective truncation of RelA/p65. Opposing functions of RelA/p65 on AP in different cell types have been reported. For example, RelA/p65 activation in myeloid cells promotes the pathogenesis of CP but protects against chronic inflammation in acinar cells (126).

Fig 3. An example of tissue specific gene deletion. Two identical loxp sites flank several exons of p65 gene. Cre mediated recombination will remove the sequences between these two sites, causing gene truncation or deletion.

The collected data argue that NF-κB functions more generally as a central regulator of stress responses and regulates both inflammation and cell survival. Coupling stress responsiveness and anti-apoptotic pathways through the use of a common transcription factor may result in increased cell survival following stress insults (92).

Functional Roles of IKK1 (IKKα)

IκB kinase α (IKKα) is a subunit of the IKK complex, which functions together with IKKβ and IKKγ/NEMO. Although it is involved in the regulation of NK-κB activity by phosphorylation of IκB proteins, which triggers their degradation, IKKα is not required for degradation of IκB by proinflammatory stimuli. IKKα is more important in alternative NF-κB signaling in which RelB:p52 dimers are activated (46). Global loss of IKKα perturbs multiple morphogenetic events, including limb and skeletal patterning and the proliferation and differentiation of epidermal keratinocytes (46, 55, 107). Pancreatic-specific IKKα ablation (using PDX-CRE) results in acinar cell vacuolization and death, fibrosis, and inflammation, resembling chronic pancreatitis in humans. These studies support that IKKα plays a critical role in maintaining pancreatic acinar cell homeostasis (74, 75). The role of IKKα in maintaining pancreatic homeostasis is independent of NF-κB or its protein kinase activity reflected in inactive IKK1 knock-in mutant mice, which exhibit no pancreatic abnormalities. In contrast, the loss of IKKα in acinar cells diminished autophagic protein degradation and caused the accumulation of p62 aggregates and ER stress. Pancreatic specific p62 ablation ameliorated pancreatitis in IKKα deficient mice (74).

IκB-α Mutation/Deletion and Pancreatitis

One of the key target genes induced by NF-κB is its inhibitor IκBα, which in turn inhibits NF-κB activity and thus establishes a feedback regulation mechanism for controlling NF-κB activity (120). Therefore, IκB-α deficiency results in a sustained NF-κB response and severe widespread dermatitis in mice (67). Although they appear normal at birth, IκB-α-/- mice exhibit severe runting, skin defects, and extensive granulopoiesis postnatally and typically die after 8 days (12).

In a mouse model where the two well-defined κB enhancer elements and four additional κB-like sites in the IκBα promoter were altered  and therefore defective in response to NF-κB activation-induced negative feedback, the mice became sick, had elevated serum cytokine levels, and died at 13 to 15 months of age.  These mice were found to be hypersensitive to LPS-induced proinflammatory cytokine production and lethality.  Pancreas, liver, and lung tissues derived from these mice at 3 months of age showed extensive perivascular lymphocytic infiltration. Immunohistochemical analysis revealed a phenotype resembling Sjögren’s syndrome, an autoimmune disorder (99).

Pancreas-specific ablation of IκB-α also led to increased basal NF-κB activity with small increases in cytokine and chemokine levels. In stark contrast, the basal increase of NF-κB did not cause any overt phenotype in the pancreas but caerulein- and L-arginine–induced pancreatitis was ameliorated in IΚB-α^-/- mice (89). The amelioration of pancreatitis was lost in the mice when p65 was also ablated, supporting that the protective effects of IκB deletion were through p65.  These results were consistent with this group’s previous study reporting that pancreas-specific RelA/p65 truncation increases the susceptibility of acini to inflammation-associated cell death following caerulein-induced pancreatitis (6). They concluded that acinar cell NF-κB activation exerts a protective role in AP.

In summary, NF-κB regulates both cell survival and inflammation. The extent, mode of NF-κB manipulation, and cellular context can have profoundly different consequences.  The paradox that activation of IKK2 or p65 leads to both aggravation and amelioration of pancreatitis reflects the complicated roles of NF-κB signaling. The complexities of NF-κB system, in both pro- and anti-inflammatory effects, have been discussed in an editorial (43).

Ras Signaling and Pancreatitis

Ras proteins function as binary molecular switches that, when turned on by occupancy with GTP, interact with downstream signaling molecules to activate a wide variety of intracellular signaling networks regulating proliferation, differentiation, apoptosis, and cell migration (56).  Ras mutations lead to increased Ras activity and are observed in ~30% of all cancers. In particular, K-Ras mutations are found in nearly every pancreatic cancer, which is the fourth leading cause of cancer-related death in USA (117). The mutant Ras is oncogenic as has been shown in many in vivo and in vitro studies (119). However, its role in the development of inflammation and fibrosis has not been well appreciated until recently (24, 64, 76).

It is well known that activating Ras mutations can induce either proliferation at low activity or senescence at high-activity levels. In mice bearing targeted pancreas-specific activating mutations at the native K-Ras locus, which increases Ras activity at lower level, pancreatic histology was normal at early stages. Only a minor subset of cells displayed hyperproliferation and tumorigenesis when the levels of Ras activity were significantly elevated (2). Evidence for the existence of a threshold of Ras pathway activity in pancreatic pathology comes from studies expressing higher levels of mutant K-Ras using a transgenic approach (Fig. 4A) (64). Although the expression of endogenous levels of mutant K-Ras results in minimal change in the pancreas, higher levels of expression generate Ras pathway activity that mimics what is observed in pancreatic cancer cells. In this model, increased Ras activity in pancreatic acinar cells caused rapid and abundant development of inflammatory cell infiltration, fibrosis, acinar cell loss, and atrophy. This model confirms that elevated levels of Ras activity are sufficient to cause chronic pancreatitis-like changes. These data suggest that the activity level of the Ras pathway, rather than the presence of mutations, is biologically important.

Transgenic overexpression of mutant K-Ras provides proof-of-concept that high Ras activity will cause an inflammatory response with drastic fibrosis. However, under physiological conditions, human or mice with knock-in mutant Ras only express endogenous levels of mutant K-Ras. While the expression of oncogenic Ras at physiological levels using a K-Ras knock-in model generally does not directly cause pathological outcomes (Fig. 4B) (52), the presence of mutations predispose Ras activity to be further significantly elevated by various etiologic stimulations (24).

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