Skip to main content
NCBI home page
Gut logoLink to Gut
. 2000 Oct;47(4):546–552. doi: 10.1136/gut.47.4.546

Inflammatory mediators in human acute pancreatitis: clinical and pathophysiological implications

J Mayer 1, B Rau 1, F Gansauge 1, H Beger 1
PMCID: PMC1728074  PMID: 10986216

Abstract

BACKGROUND—The time course and relationship between circulating and local cytokine concentrations, pancreatic inflammation, and organ dysfunction in acute pancreatitis are largely unknown.
PATIENTS AND METHODS—In a prospective clinical study, we measured the proinflammatory cytokines interleukin (IL)-1β, IL-6 and IL-8, the anti-inflammatory cytokine IL-10, interleukin 1β receptor antagonist (IL-1RA), and the soluble IL-2 receptor (sIL-2R), and correlated our findings with organ and systemic complications in acute pancreatitis. In 51 patients with acute pancreatitis admitted within 72 hours after the onset of symptoms, these parameters were measured daily for seven days. In addition, 33 aspirates from ascites and the lesser sac were measured.
RESULTS—Sixteen patients had mild acute pancreatitis (AP) and 35 severe AP (Atlanta classification); 18 patients developed systemic complications requiring treatment. All mediators were increased in AP. sIL-2R, IL-10, and IL-6 were significantly elevated in patients with distant organ failure. An imbalance in IL-1β/IL-1RA was found in severe AP and pulmonary failure. Peak serum sIL-2R predicted lethal outcome and IL-1RA was an early marker of severity. IL-6 was the best prognostic parameter for pulmonary failure.
CONCLUSION—Our results suggest that local mediator release, with a probable IL-1β-IL-1RA imbalance in severe cases, is followed by the systemic appearance of pro- and anti-inflammatory mediators. The pattern of local and systemic mediators in complicated AP suggests a role for systemic lymphocyte activation (triggered by local release of mediators) in distant organ complications in severe AP.


Keywords: pancreatitis; cytokines; lymphocyte activation; pancreatic necrosis; organ complications

Full Text

The Full Text of this article is available as a PDF (164.0 KB).

Figure 1  .

Figure 1  

Open in a new tab

Time course of the proinflammatory mediators (interleukins (IL)-1β, IL-6, and IL-8, and soluble interleukin 2 receptor (sIL-2R)) in serum in human acute pancreatitis. Values are median (interquartile range). SAP, severe acute pancreatitis; MAP, mild acute pancreatitis.

Figure 2  .

Figure 2  

Open in a new tab

Time course of the anti-inflammatory mediators (interleukin 10 (IL-10) and interleukin 1β receptor antagonist (IL-1RA)) in serum in human acute pancreatitis. Values are median (interquartile range). SAP, severe acute pancreatitis; MAP, mild acute pancreatitis.

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Berney T., Gasche Y., Robert J., Jenny A., Mensi N., Grau G., Vermeulen B., Morel P. Serum profiles of interleukin-6, interleukin-8, and interleukin-10 in patients with severe and mild acute pancreatitis. Pancreas. 1999 May;18(4):371–377. doi: 10.1097/00006676-199905000-00007. [DOI] [PubMed] [Google Scholar]
  2. Bradley E. L., 3rd A clinically based classification system for acute pancreatitis. Summary of the International Symposium on Acute Pancreatitis, Atlanta, Ga, September 11 through 13, 1992. Arch Surg. 1993 May;128(5):586–590. doi: 10.1001/archsurg.1993.01420170122019. [DOI] [PubMed] [Google Scholar]
  3. Brivet F. G., Emilie D., Galanaud P. Pro- and anti-inflammatory cytokines during acute severe pancreatitis: an early and sustained response, although unpredictable of death. Parisian Study Group on Acute Pancreatitis. Crit Care Med. 1999 Apr;27(4):749–755. doi: 10.1097/00003246-199904000-00029. [DOI] [PubMed] [Google Scholar]
  4. Chen C. C., Wang S. S., Lu R. H., Chang F. Y., Lee S. D. Serum interleukin 10 and interleukin 11 in patients with acute pancreatitis. Gut. 1999 Dec;45(6):895–899. doi: 10.1136/gut.45.6.895. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Curley P. J., McMahon M. J., Lancaster F., Banks R. E., Barclay G. R., Shefta J., Boylston A. W., Whicher J. T. Reduction in circulating levels of CD4-positive lymphocytes in acute pancreatitis: relationship to endotoxin, interleukin 6 and disease severity. Br J Surg. 1993 Oct;80(10):1312–1315. doi: 10.1002/bjs.1800801031. [DOI] [PubMed] [Google Scholar]
  6. Denham W., Denham D., Yang J., Carter G., MacKay S., Moldawer L. L., Carey L. C., Norman J. Transient human gene therapy: a novel cytokine regulatory strategy for experimental pancreatitis. Ann Surg. 1998 Jun;227(6):812–820. doi: 10.1097/00000658-199806000-00004. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Denham W., Yang J., Fink G., Denham D., Carter G., Ward K., Norman J. Gene targeting demonstrates additive detrimental effects of interleukin 1 and tumor necrosis factor during pancreatitis. Gastroenterology. 1997 Nov;113(5):1741–1746. doi: 10.1053/gast.1997.v113.pm9352880. [DOI] [PubMed] [Google Scholar]
  8. Donnelly S. C., Strieter R. M., Kunkel S. L., Walz A., Robertson C. R., Carter D. C., Grant I. S., Pollok A. J., Haslett C. Interleukin-8 and development of adult respiratory distress syndrome in at-risk patient groups. Lancet. 1993 Mar 13;341(8846):643–647. doi: 10.1016/0140-6736(93)90416-e. [DOI] [PubMed] [Google Scholar]
  9. Farkas G., Márton J., Nagy Z., Mándi Y., Takács T., Deli M. A., Abrahám C. S. Experimental acute pancreatitis results in increased blood-brain barrier permeability in the rat: a potential role for tumor necrosis factor and interleukin 6. Neurosci Lett. 1998 Feb 20;242(3):147–150. doi: 10.1016/s0304-3940(98)00060-3. [DOI] [PubMed] [Google Scholar]
  10. Fink G. W., Norman J. G. Intrapancreatic interleukin-1beta gene expression by specific leukocyte populations during acute pancreatitis. J Surg Res. 1996 Jun;63(1):369–373. doi: 10.1006/jsre.1996.0278. [DOI] [PubMed] [Google Scholar]
  11. Fink G. W., Norman J. G. Specific changes in the pancreatic expression of the interleukin 1 family of genes during experimental acute pancreatitis. Cytokine. 1997 Dec;9(12):1023–1027. doi: 10.1006/cyto.1997.0260. [DOI] [PubMed] [Google Scholar]
  12. Formela L. J., Galloway S. W., Kingsnorth A. N. Inflammatory mediators in acute pancreatitis. Br J Surg. 1995 Jan;82(1):6–13. doi: 10.1002/bjs.1800820105. [DOI] [PubMed] [Google Scholar]
  13. Geissler K. Current status of clinical development of interleukin-10. Curr Opin Hematol. 1996 May;3(3):203–208. doi: 10.1097/00062752-199603030-00007. [DOI] [PubMed] [Google Scholar]
  14. Gross V., Andreesen R., Leser H. G., Ceska M., Liehl E., Lausen M., Farthmann E. H., Schölmerich J. Interleukin-8 and neutrophil activation in acute pancreatitis. Eur J Clin Invest. 1992 Mar;22(3):200–203. doi: 10.1111/j.1365-2362.1992.tb01826.x. [DOI] [PubMed] [Google Scholar]
  15. Heath D. I., Cruickshank A., Gudgeon A. M., Jehanli A., Shenkin A., Imrie C. W. The relationship between pancreatic enzyme release and activation and the acute-phase protein response in patients with acute pancreatitis. Pancreas. 1995 May;10(4):347–353. doi: 10.1097/00006676-199505000-00005. [DOI] [PubMed] [Google Scholar]
  16. Heresbach D., Letourneur J. P., Bahon I., Pagenault M., Guillou Y. M., Dyard F., Fauchet R., Mallédant Y., Bretagne J. F., Gosselin M. Value of early blood Th-1 cytokine determination in predicting severity of acute pancreatitis. Scand J Gastroenterol. 1998 May;33(5):554–560. doi: 10.1080/00365529850172160. [DOI] [PubMed] [Google Scholar]
  17. Hynninen M., Valtonen M., Markkanen H., Vaara M., Kuusela P., Jousela I., Piilonen A., Takkunen O. Interleukin 1 receptor antagonist and E-selectin concentrations: a comparison in patients with severe acute pancreatitis and severe sepsis. J Crit Care. 1999 Jun;14(2):63–68. doi: 10.1016/s0883-9441(99)90015-1. [DOI] [PubMed] [Google Scholar]
  18. Inagaki T., Hoshino M., Hayakawa T., Ohara H., Yamada T., Yamada H., Iida M., Nakazawa T., Ogasawara T., Uchida A. Interleukin-6 is a useful marker for early prediction of the severity of acute pancreatitis. Pancreas. 1997 Jan;14(1):1–8. doi: 10.1097/00006676-199701000-00001. [DOI] [PubMed] [Google Scholar]
  19. Kingsnorth A. Role of cytokines and their inhibitors in acute pancreatitis. Gut. 1997 Jan;40(1):1–4. doi: 10.1136/gut.40.1.1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Kusske A. M., Rongione A. J., Ashley S. W., McFadden D. W., Reber H. A. Interleukin-10 prevents death in lethal necrotizing pancreatitis in mice. Surgery. 1996 Aug;120(2):284–289. doi: 10.1016/s0039-6060(96)80299-6. [DOI] [PubMed] [Google Scholar]
  21. Mayer J., Laine V. J., Rau B., Hotz H. G., Foitzik T., Nevalainen T. J., Beger H. G. Systemic lymphocyte activation modulates the severity of diet-induced acute pancreatitis in mice. Pancreas. 1999 Jul;19(1):62–68. doi: 10.1097/00006676-199907000-00010. [DOI] [PubMed] [Google Scholar]
  22. McKay C. J., Gallagher G., Brooks B., Imrie C. W., Baxter J. N. Increased monocyte cytokine production in association with systemic complications in acute pancreatitis. Br J Surg. 1996 Jul;83(7):919–923. doi: 10.1002/bjs.1800830712. [DOI] [PubMed] [Google Scholar]
  23. Norman J. G., Fink G. W., Denham W., Yang J., Carter G., Sexton C., Falkner J., Gower W. R., Franz M. G. Tissue-specific cytokine production during experimental acute pancreatitis. A probable mechanism for distant organ dysfunction. Dig Dis Sci. 1997 Aug;42(8):1783–1788. doi: 10.1023/a:1018886120711. [DOI] [PubMed] [Google Scholar]
  24. Norman J. G., Fink G. W., Sexton C., Carter G. Transgenic animals demonstrate a role for the IL-1 receptor in regulating IL-1beta gene expression at steady-state and during the systemic stress induced by acute pancreatitis. J Surg Res. 1996 Jun;63(1):231–236. doi: 10.1006/jsre.1996.0253. [DOI] [PubMed] [Google Scholar]
  25. Norman J. G., Franz M. G., Fink G. S., Messina J., Fabri P. J., Gower W. R., Carey L. C. Decreased mortality of severe acute pancreatitis after proximal cytokine blockade. Ann Surg. 1995 Jun;221(6):625–634. doi: 10.1097/00000658-199506000-00002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Norman J., Franz M., Messina J., Riker A., Fabri P. J., Rosemurgy A. S., Gower W. R., Jr Interleukin-1 receptor antagonist decreases severity of experimental acute pancreatitis. Surgery. 1995 Jun;117(6):648–655. doi: 10.1016/s0039-6060(95)80008-5. [DOI] [PubMed] [Google Scholar]
  27. Norman J. The role of cytokines in the pathogenesis of acute pancreatitis. Am J Surg. 1998 Jan;175(1):76–83. doi: 10.1016/s0002-9610(97)00240-7. [DOI] [PubMed] [Google Scholar]
  28. Norman J., Yang J., Fink G., Carter G., Ku G., Denham W., Livingston D. Severity and mortality of experimental pancreatitis are dependent on interleukin-1 converting enzyme (ICE). J Interferon Cytokine Res. 1997 Feb;17(2):113–118. doi: 10.1089/jir.1997.17.113. [DOI] [PubMed] [Google Scholar]
  29. Pezzilli R., Billi P., Gullo L., Beltrandi E., Maldini M., Mancini R., Incorvaia L., Miglioli M. Behavior of serum soluble interleukin-2 receptor, soluble CD8 and soluble CD4 in the early phases of acute pancreatitis. Digestion. 1994;55(4):268–273. doi: 10.1159/000201159. [DOI] [PubMed] [Google Scholar]
  30. Pezzilli R., Billi P., Miniero R., Barakat B. Serum interleukin-10 in human acute pancreatitis. Dig Dis Sci. 1997 Jul;42(7):1469–1472. doi: 10.1023/a:1018814710291. [DOI] [PubMed] [Google Scholar]
  31. Pezzilli R., Billi P., Miniero R., Fiocchi M., Cappelletti O., Morselli-Labate A. M., Barakat B., Sprovieri G., Miglioli M. Serum interleukin-6, interleukin-8, and beta 2-microglobulin in early assessment of severity of acute pancreatitis. Comparison with serum C-reactive protein. Dig Dis Sci. 1995 Nov;40(11):2341–2348. doi: 10.1007/BF02063235. [DOI] [PubMed] [Google Scholar]
  32. Pezzilli R., Morselli-Labate A. M., Miniero R., Barakat B., Fiocchi M., Cappelletti O. Simultaneous serum assays of lipase and interleukin-6 for early diagnosis and prognosis of acute pancreatitis. Clin Chem. 1999 Oct;45(10):1762–1767. [PubMed] [Google Scholar]
  33. Pietra N., Sarli L., Caruana P., Cabras A., Costi R., Gobbi S., Bordi C., Peracchia A. Is tumour angiogenesis a prognostic factor in patients with colorectal cancer and no involved nodes? Eur J Surg. 2000 Jul;166(7):552–556. doi: 10.1080/110241500750008628. [DOI] [PubMed] [Google Scholar]
  34. Rau B., Steinbach G., Gansauge F., Mayer J. M., Grünert A., Beger H. G. The potential role of procalcitonin and interleukin 8 in the prediction of infected necrosis in acute pancreatitis. Gut. 1997 Dec;41(6):832–840. doi: 10.1136/gut.41.6.832. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Rongione A. J., Kusske A. M., Kwan K., Ashley S. W., Reber H. A., McFadden D. W. Interleukin 10 reduces the severity of acute pancreatitis in rats. Gastroenterology. 1997 Mar;112(3):960–967. doi: 10.1053/gast.1997.v112.pm9041259. [DOI] [PubMed] [Google Scholar]
  36. Tanaka N., Murata A., Uda K., Toda H., Kato T., Hayashida H., Matsuura N., Mori T. Interleukin-1 receptor antagonist modifies the changes in vital organs induced by acute necrotizing pancreatitis in a rat experimental model. Crit Care Med. 1995 May;23(5):901–908. doi: 10.1097/00003246-199505000-00019. [DOI] [PubMed] [Google Scholar]
  37. Tompkins R. G. The role of proinflammatory cytokines in inflammatory and metabolic responses. Ann Surg. 1997 Mar;225(3):243–245. doi: 10.1097/00000658-199703000-00001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Uhl W., Büchler M., Malfertheiner P., Martini M., Beger H. G. PMN-elastase in comparison with CRP, antiproteases, and LDH as indicators of necrosis in human acute pancreatitis. Pancreas. 1991 May;6(3):253–259. doi: 10.1097/00006676-199105000-00001. [DOI] [PubMed] [Google Scholar]
  39. Van Laethem J. L., Marchant A., Delvaux A., Goldman M., Robberecht P., Velu T., Devière J. Interleukin 10 prevents necrosis in murine experimental acute pancreatitis. Gastroenterology. 1995 Jun;108(6):1917–1922. doi: 10.1016/0016-5085(95)90158-2. [DOI] [PubMed] [Google Scholar]
  40. Viedma J. A., Pérez-Mateo M., Domínguez J. E., Carballo F. Role of interleukin-6 in acute pancreatitis. Comparison with C-reactive protein and phospholipase A. Gut. 1992 Sep;33(9):1264–1267. doi: 10.1136/gut.33.9.1264. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Widdison A. L., Cunningham S. Immune function early in acute pancreatitis. Br J Surg. 1996 May;83(5):633–636. doi: 10.1002/bjs.1800830514. [DOI] [PubMed] [Google Scholar]
  42. de Beaux A. C., Ross J. A., Maingay J. P., Fearon K. C., Carter D. C. Proinflammatory cytokine release by peripheral blood mononuclear cells from patients with acute pancreatitis. Br J Surg. 1996 Aug;83(8):1071–1075. doi: 10.1002/bjs.1800830811. [DOI] [PubMed] [Google Scholar]

Articles from Gut are provided here courtesy of BMJ Publishing Group

RESOURCES