This Key Event Relationship is licensed under the Creative Commons BY-SA license. This license allows reusers to distribute, remix, adapt, and build upon the material in any medium or format, so long as attribution is given to the creator. The license allows for commercial use. If you remix, adapt, or build upon the material, you must license the modified material under identical terms.

Relationship: 2030


A descriptive phrase which clearly defines the two KEs being considered and the sequential relationship between them (i.e., which is upstream, and which is downstream). More help

Increased blood CCK level leads to Increased acinar cell exocrine secretion

Upstream event
The causing Key Event (KE) in a Key Event Relationship (KER). More help
Downstream event
The responding Key Event (KE) in a Key Event Relationship (KER). More help

Key Event Relationship Overview

The utility of AOPs for regulatory application is defined, to a large extent, by the confidence and precision with which they facilitate extrapolation of data measured at low levels of biological organisation to predicted outcomes at higher levels of organisation and the extent to which they can link biological effect measurements to their specific causes.Within the AOP framework, the predictive relationships that facilitate extrapolation are represented by the KERs. Consequently, the overall WoE for an AOP is a reflection in part, of the level of confidence in the underlying series of KERs it encompasses. Therefore, describing the KERs in an AOP involves assembling and organising the types of information and evidence that defines the scientific basis for inferring the probable change in, or state of, a downstream KE from the known or measured state of an upstream KE. More help

AOPs Referencing Relationship

AOP Name Adjacency Weight of Evidence Quantitative Understanding Point of Contact Author Status OECD Status
Trypsin inhibition leading to pancreatic acinar cell tumors adjacent High High Shigeru Hisada (send email) Under development: Not open for comment. Do not cite Under Development

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) that help to define the biological applicability domain of the KER.In general, this will be dictated by the more restrictive of the two KEs being linked together by the KER.  More help
Term Scientific Term Evidence Link
Homo sapiens Homo sapiens High NCBI
Macaca fascicularis Macaca fascicularis High NCBI
Rattus norvegicus Rattus norvegicus High NCBI
Mus musculus Mus musculus High NCBI

Sex Applicability

An indication of the the relevant sex for this KER. More help
Sex Evidence
Mixed High

Life Stage Applicability

An indication of the the relevant life stage(s) for this KER.  More help
Term Evidence
All life stages High

Key Event Relationship Description

Provides a concise overview of the information given below as well as addressing details that aren’t inherent in the description of the KEs themselves. More help

Pancreatic exocrine secretion is regulated mainly by cholecystokinin (CCK) released by CCK-producing I cells located in the mucosa of the upper small intestine. CCK stimulates exocrine secretion directly via CCK receptors expressed on acinar cell surfaces or indirectly via vagal afferent nerves expressing CCK receptors.

There are two types of CCK receptors: CCK1 (CCK-A) and CCK2 (CCK-B or gastrin) receptors. The former shows high affinity to CCK and the latter to both CCK and gastrin [Wang BJ and Cui ZJ, 2007; Dufresne M et al, 2006].

There are species differences in CCK-mediated pancreatic exocrine secretion. In rats, exocrine secretion from pancreatic acinar cells is regulated directly by CCK1 receptors expressed on the surface of acinar cells and indirectly by vagal afferent nerves expressing CCK1 receptors. Meanwhile, in humans, pancreatic exocrine secretion is regulated mainly by vagal afferent nerves expressing CCK1 receptors [Wang BJ and Cui ZJ, 2007].

The major function of pancreatic exocrine secretion is the production and secretion of digestive enzymes. Zymogen granules located at the apical site of pancreatic acinar cells contain the precursors of multiple digestive enzymes such as trypsinogen, chymotrypsinogen, proesterases, procarboxypeptidase A and B, as well as pancreatic lipase and amylase α. These precursors are secreted by acinar cells into the small intestine, where they are activated by pepsins and peptidases [Berg JM et al, 2002].

Evidence Collection Strategy

Include a description of the approach for identification and assembly of the evidence base for the KER. For evidence identification, include, for example, a description of the sources and dates of information consulted including expert knowledge, databases searched and associated search terms/strings.  Include also a description of study screening criteria and methodology, study quality assessment considerations, the data extraction strategy and links to any repositories/databases of relevant references.Tabular summaries and links to relevant supporting documentation are encouraged, wherever possible. More help

Evidence Supporting this KER

Addresses the scientific evidence supporting KERs in an AOP setting the stage for overall assessment of the AOP. More help


Biological Plausibility
Addresses the biological rationale for a connection between KEupstream and KEdownstream.  This field can also incorporate additional mechanistic details that help inform the relationship between KEs, this is useful when it is not practical/pragmatic to represent these details as separate KEs due to the difficulty or relative infrequency with which it is likely to be measured.   More help

Pancreatic exocrine secretion

The major function of pancreatic exocrine secretion is the release of digestive enzymes, fluid, and bicarbonate in response to food intake. Zymogen granules located at the apical site of pancreatic acinar cells contain the precursors of multiple digestive enzymes, such as trypsinogen, chymotrypsinogen, proesterase, procarboxypeptidase A and B, as well as pancreatic lipase and amylase α. These precursors are secreted into the small intestine, where trypsinogen is converted to trypsin by enteropeptidase, and the newly generated trypsin activates more trypsinogen molecules and other proenzymes [Berg JM et al, 2002].

Regulation of pancreatic exocrine secretion via CCK and CCK receptors

Pancreatic exocrine secretion is regulated mainly by CCK released from CCK-producing I cells located within the mucosa of the small intestine. CCK stimulates exocrine secretion either directly via CCK receptors expressed on acinar cells or indirectly by the vagovagal reflex via CCK receptors. There are species differences in these CCK regulatory mechanisms [Singer MV and Niebergall-Roth E, 2009; Chandra R and Liddle RA, 2009].

CCK receptor subtypes

There are two types of CCK receptors: CCK1 (CCK-A) and CCK2 (CCK-B or gastrin receptor) receptors. The CCK1 receptor exhibits high affinity to all CCK isoforms, whereas the CCK2 receptor exhibits affinity to both CCKs and gastrin [Dufresne M et al, 2006; Rehfeld JF, 2017].

Direct and indirect innervation-mediated regulation of exocrine secretion from acinar cells via CCK receptors

In rats, pancreatic acinar cells express mainly CCK1 receptors, and blood CCK directly stimulates exocrine secretion and acinar cell proliferation [Dufresne M et al, 2006]. Moreover, the vagal afferent nerves also stimulate pancreatic exocrine secretion; CCK stimulates CCK1 receptors expressed on the vagal afferent nerve fibers of the vago–vagal loop, and the acetylcholine generated acts on M3 muscarinic cholinergic receptors to promote pancreatic exocrine secretion [Bourassa J et al, 1999; Adler G, 1997; Ji B et al, 2001; Li Y et al, 1997; Owyang C, 1996].

In humans, the density of CCK receptors expressed on acinar cells is lower than that in rodents, whereas CCK2 receptors are dominantly expressed. Therefore, the responses of acinar cells to CCK seem to be weaker compared with rodents, and pancreatic exocrine secretion in humans is regulated mainly by vagal afferent nerves expressing CCK1 receptors [Wang BJ and Cui ZJ, 2007; Owyang C, 1996; Pandiri AR, 2014].

Uncertainties and Inconsistencies
Addresses inconsistencies or uncertainties in the relationship including the identification of experimental details that may explain apparent deviations from the expected patterns of concordance. More help


Known modulating factors

This table captures specific information on the MF, its properties, how it affects the KER and respective references.1.) What is the modulating factor? Name the factor for which solid evidence exists that it influences this KER. Examples: age, sex, genotype, diet 2.) Details of this modulating factor. Specify which features of this MF are relevant for this KER. Examples: a specific age range or a specific biological age (defined by...); a specific gene mutation or variant, a specific nutrient (deficit or surplus); a sex-specific homone; a certain threshold value (e.g. serum levels of a chemical above...) 3.) Description of how this modulating factor affects this KER. Describe the provable modification of the KER (also quantitatively, if known). Examples: increase or decrease of the magnitude of effect (by a factor of...); change of the time-course of the effect (onset delay by...); alteration of the probability of the effect; increase or decrease of the sensitivity of the downstream effect (by a factor of...) 4.) Provision of supporting scientific evidence for an effect of this MF on this KER. Give a list of references.  More help

Disruption of the CCK1 receptor in rats also affects pancreatic exocrine secretion [Miyasaka K et al, 1998].

Capsaicin and atropine inhibit cholinergic vagus nerve reflexes to reduce CCK-mediated pancreatic enzyme secretion [Li Y et al, 1997; Yamamoto M et al, 2003; Li Y and Owyang C, 1994; Soudah HC et al, 1992; Owyang C et al, 1986].

Response-response Relationship
Provides sources of data that define the response-response relationships between the KEs.  More help

CCK action on the stimulation of pancreatic secretion is dose dependent. Doses of CCK that induce physiological concentrations of plasma CCK (up to ~10 pM) stimulate the vagal afferent pathway, whereas doses that produce supraphysiological CCK levels act to stimulate intrapancreatic neurons and pancreatic acini. The brief summaries are as follows:

Intravenous infusion of CCK-8 at 20 and 40 pM/kg/hour or high affinity CCKR agonist CCK-JMV-189 at 22, 44 and 88 μg/kg/hour in rats induced dose-dependent increases in pancreatic protein secretion from 15 minutes of infusion, which was blocked by the CCK1 receptor antagonist L-364,718 [Li Y et al, 1997].

Physiological level of plasma CCK (up to ~10 pM) result in stimulation of the vagal afferent pathway originating from the gastroduodenal mucosa, whereas doses that induce supraphysiological CCK levels result in stimulation of intrapancreatic neurons and pancreatic acini [Owyang C, 1996].

Information regarding the approximate time-scale of the changes in KEdownstream relative to changes in KEupstream (i.e., do effects on KEdownstream lag those on KEupstream by seconds, minutes, hours, or days?). More help

In rats in which bile and pancreatic juice had been returned to the duodenum, intraduodenal administration of 30 mg RSF stimulated a 1-h integrated increase in pancreatic protein output of 2.2 ± 1.1 mg/h (mean ± SE) [Jordinson M et al, 1996].

Bile-pancreatic juice diversion in rats increases pancreatic protein secretion with more than two fold 60 minutes after the start of diversion with elevated blood level of CCK [Li Y and Owyang C, 1994].

Intravenous infusion of CCK at 60 IU/kg/hour induces the pancreatic secretion of amylase and trypsin with peak level at 45 minutes after the start of the stimulation [Folsch UR et al, 1978].

In human intraduodenal perfusion of phenylalanine at 10mM, 5mL/min induced a several times increase in the plasma level of CCK within 15 minutes and a four-times increase in one-hour pancreatic outputs of trypsin and chymotrypsin. Intravenous infusion of CCK-8 at 20 and 40 ng/kg/h for 60 minutes showed a dose-dependent increase in pancreatic output of chymotrypsin [Owyang C et al, 1986].

These results suggest that CCK-induced pancreatic exocrine secretion occur within a short time after CCK infusion or stimulation of CCK release.

Known Feedforward/Feedback loops influencing this KER
Define whether there are known positive or negative feedback mechanisms involved and what is understood about their time-course and homeostatic limits. More help


Domain of Applicability

A free-text section of the KER description that the developers can use to explain their rationale for the taxonomic, life stage, or sex applicability structured terms. More help

Species differences in the mechanism of CCK release

Pancreatic exocrine secretion is controlled mainly by CCK released into the blood steam from intestinal mucosal I cells of the small intestine in response to the gastric contents transported to the intestine [Singer MV and Niebergall-Roth E, 2009; Rehfeld JF, 2017]. Peptides released from gastrointestinal digestion, along with fatty acids, are the main stimuli of CCK release involving several direct and indirect pathways [Caron J et al, 2017].

In humans and canines, amino acids and fatty acids in the gastric contents transported to the small intestine play a major role in stimulating CCK release, which regulates pancreatic exocrine secretion, but MP is not involved in exocrine regulation [Wang BJ and Cui ZJ, 2007]. CCK-stimulated pancreatic exocrine secretion seems to be regulated with negative feedback manner via LCRF.

In rats, however, different from other mammalian species, nutrient protein and protein hydrolysate stimulate CCK release and MP secreted by pancreatic acinar cells plays an active role in protein/protein hydrolysate-stimulated CCK release [Iwai K et al, 1988; Fushiki T et al, 1989]. Ingestion of trypsin inhibitors increases the intestinal level of MP, especially after all nutrient protein is digested in the intestines, causing a subsequent increase in the blood level of CCK. The increased CCK level stimulates pancreatic exocrine secretion of proteins including MP, which in turn further increases the release of CCK. This positive feedback response associated with MP secretion might lead to continuously elevated plasma levels of CCK [Liddle RA, 1995].

Species differences in CCKs

Several isoforms of CCK, including CCK-83, -58, -39, -33, -22, and -8, have been identified, and there are species differences in CCK isoforms (e.g., CCK-33, -22 and -58 are expressed in humans, CCK-58 in dogs, CCK-8, -33 and -58 in cats, CCK-22, -58, -3 and -8 in pigs, CCK-22 and -8 in rabbits, and CCK-58 in rats). All of these CCK isoforms have a highly conserved region of amino acids, and all are ligands of CCK1 receptors [Wang BJ and Cui ZJ, 2007].

Species differences in pancreatic exocrine secretion

In rats, CCK stimulates pancreatic exocrine secretion and acinar cell growth directly via CCK1 receptors expressed on the cell surface, and exocrine secretion is also innervated by vagal afferent nerves expressing CCK1 receptors [Singer MV and Niebergall-Roth E, 2009; Pandiri AR, 2014; Yamamoto M et al, 2003].

On the other hand, human pancreatic acinar cells do not express CCK1 receptors, and CCK-mediated exocrine secretion is regulated exclusively by innervation of vagal nerves expressing CCK1 receptors [Soudah HC et al, 1992; Beglinger C et al, 1992; Singer MV and Niebergall-Roth E, 2009], although there is some evidence of direct stimulation of exocrine secretion of human pancreatic acinar cells [Murphy JA et al, 2008].

Species differences in CCK receptors

CCK1 and CCK2 receptors are expressed in various organs and tissues including digestive and nervous systems, and there are species differences in distribution and expression levels of the receptors.

In rats, pancreatic acinar cells express mainly CCK1 receptors and no CCK2 receptors [Bourassa J et al, 1999]. CCK1 receptors are also expressed in vagal afferent nerve fibers of the gastroduodenal tract. Stimulation of the vagal nerve via CCK1 receptors as well as via physical stimulation by stomach wall distention from ingested food also promotes pancreatic exocrine secretion [Dufresne M et al, 2006].

In humans, on the other hand, CCK2 receptors are dominantly expressed in pancreatic acinar cells, with low expression of CCK1 receptors [Nishimori I et al, 1999]. Ji reported the following: 1) the mRNA level of the CCK2 receptor is higher than that of the CCK1 receptor in the human pancreas; 2) an in situ hybridization experiment showed no expression of either receptor type in the human pancreas, and 3) human pancreatic cells did not show any response to the CCK1 receptor agonist CCK8 or the CCK2 receptor agonist gastrin in vitro [Ji B et al, 2001]. Therefore, human pancreatic acinar cells respond to CCK more weakly compared with the response in rodents.

Although the distribution of CCK receptors is different between humans and rodents, the structures of CCK1 receptors are highly conserved among mammalian species, with 98% homology between rats and mice, 90% between rats and humans, 98% between cynomolgus monkeys and humans, and 89% between dogs and humans [Wang BJ and Cui ZJ, 2007].


List of the literature that was cited for this KER description. More help

 1.    Adler G: Regulation of human pancreatic secretion. Digestion 58 Suppl 1:39-41,1997

 2.    Beglinger C, Hildebrand P, Adler G, Werth B, Luo H, Delco F, Gyr K: Postprandial control of gallbladder contraction and exocrine pancreatic secretion in man. Eur J Clin Invest 22:827-834,1992

 3.    Berg JM, Tymoczko JL, Stryer L: Many enzymes are activated by specific proteolytic cleavage. Biochemistry. 5th edition. New York: W H Freeman, Section 10.5,2002

 4.    Bourassa J, Laine J, Kruse ML, Gagnon MC, Calvo E, Morisset J: Ontogeny and species differences in the pancreatic expression and localization of the CCK(A) receptors. Biochem Biophys Res Commun 260:820-828,1999

 5.    Caron J, Domenger D, Dhulster P, Ravallec R, Cudennec B: Protein digestion-derived peptides and the peripheral regulation of food intake. Front Endocrinol (Lausanne) 8:85,2017

 6.    Chandra R, Liddle RA: Neural and hormonal regulation of pancreatic secretion. Curr Opin Gastroenterol 25:441-446,2009.

 7.    Dufresne M, Seva C, Fourmy D: Cholecystokinin and gastrin receptors. Physiol Rev 86:805-847,2006

 8.    Folsch UR, Winckler K, Wormsley KG: Influence of repeated administration of cholecystokinin and secretin on the pancreas of the rat. Scand J Gastroenterol 13:663-671,1978

 9.    Fushiki T, Kajiura H, Fukuoka S, Kido K, Semba T, Iwai K: Evidence for an intraluminal mediator in rat pancreatic enzyme secretion: reconstitution of the pancreatic response with dietary protein, trypsin and the monitor peptide. J Nutr 119:622-627,1989

10.    Iwai K, Fushiki T, Fukuoka S: Pancreatic enzyme secretion mediated by novel peptide: monitor peptide hypothesis. Pancreas 3:720-728,1988

11.    Ji B, Bi Y, Simeone D, Mortensen RM, Logsdon CD: Human pancreatic acinar cells lack functional responses to cholecystokinin and gastrin. Gastroenterology 121:1380-1390,2001

12.    Jordinson M, Deprez PH, Playford RJ, Heal S, Freeman TC, Alison M, Calam J: Soybean lectin stimulates pancreatic exocrine secretion via CCK-A receptors in rats. Am J Physiol 270:G653-9,1996

13.    Li Y, Owyang C: Endogenous cholecystokinin stimulates pancreatic enzyme secretion via vagal afferent pathway in rats. Gastroenterology 107:525-531,1994

14.    Li Y, Hao Y, Owyang C: High-affinity CCK-A receptors on the vagus nerve mediate CCK-stimulated pancreatic secretion in rats. Am J Physiol 273:G679-85,1997

15.    Liddle RA: Regulation of cholecystokinin secretion by intraluminal releasing factors. Am J Physiol 269:G319-27,1995

16.    Miyasaka K, Ohta M, Tateishi K, Jimi A, Funakoshi A: Role of cholecystokinin-A (CCK-A) receptor in pancreatic regeneration after pancreatic duct occlusion: a study in rats lacking CCK-A receptor gene expression. Pancreas 16:114-123,1998

17.    Murphy JA, Criddle DN, Sherwood M, Chvanov M, Mukherjee R, McLaughlin E, Booth D, Gerasimenko JV, Raraty MG, Ghaneh P, Neoptolemos JP, Gerasimenko OV, Tepikin AV, Green GM, Reeve JR Jr, Petersen OH, Sutton R: Direct activation of cytosolic Ca2+ signaling and enzyme secretion by cholecystokinin in human pancreatic acinar cells. Gastroenterology 135:632-641,2008

18.    Nishimori I, Kamakura M, Fujikawa-Adachi K, Nojima M, Onishi S, Hollingsworth MA, Harris A: Cholecystokinin A and B receptor mRNA expression in human pancreas. Pancreas 19:109-113,1999

19.    Owyang C, May D, Louie DS: Trypsin suppression of pancreatic enzyme secretion. Differential effect on cholecystokinin release and the enteropancreatic reflex. Gastroenterology 91:637-643,1986

20.    Owyang C, Louie DS, Tatum D: Feedback regulation of pancreatic enzyme secretion. Suppression of cholecystokinin release by trypsin. J Clin Invest 77:2042-2047,1986

21.    Owyang C: Physiological mechanisms of cholecystokinin action on pancreatic secretion. Am J Physiol 271:G1-7,1996

22.    Pandiri AR: Overview of exocrine pancreatic pathobiology. Toxicol Pathol 42:207-216,2014

23.    Rehfeld JF: Cholecystokinin-from local gut hormone to ubiquitous messenger. Front Endocrinol (Lausanne) 8:47,2017

24.    Singer MV, Niebergall-Roth E: Secretion from acinar cells of the exocrine pancreas: role of enteropancreatic reflexes and cholecystokinin. Cell Biol Int 33:1-9,2009

25.    Soudah HC, Lu Y, Hasler WL, Owyang C: Cholecystokinin at physiological levels evokes pancreatic enzyme secretion via a cholinergic pathway. Am J Physiol 263:G102-107,1992

26.    Wang BJ, Cui ZJ: How does cholecystokinin stimulate exocrine pancreatic secretion? From birds, rodents, to humans. Am J Physiol Regul Integr Comp Physiol 292:R666-78,2007

27.    Yamamoto M, Otani M, Jia DM, Fukumitsu K, Yoshikawa H, Akiyama T, Otsuki M: Differential mechanism and site of action of CCK on the pancreatic secretion and growth in rats. Am J Physiol Gastrointest Liver Physiol 285:G681-687,2003