- Email: [email protected]
Elevation of serum interleukin-6 concentration precedes acute-phase response and reflects severity in acute pancreatitis
GASTROENTEROLOGY
1991;101:782-785
Elevation of Serum Interleukin-6 Concentration Precedes Acute-Phase Response and Reflects Severity in Acute Pancreatitis H.-G. LESER, V. GROSS, C. SCHEIBENBOGEN, A. HEINISCH, R. SALM, M. LAUSEN, K. RtiCKAUER, R. ANDREESEN, E. H. FARTHMANN, and J. SCHhLMERICH Departments of Ehternal Medicine and Surgery, University of Freiburg, Freiburg, Germany
Experimental studies have shown that interleukin-6 induces all major acute-phase proteins in the liver, including C-reactive protein. In 50 patients with acute pancreatitis, the serum concentrations of interleukin-6 and C-reactive protein were determined daily during the first week of hospitalization. Patients were divided into three groups according to clinical criteria: mild pancreatitis [I 1 complication; (2 2 complications; n = 25), severe pancreatitis n = 15),and lethal outcome (n = 10). Patients with mild disease showed initially slightly elevated levels of interleukin-6 (22.0 + 9.8 WmL) that decreased to low levels within 4 days (5.0 k 1.0 U/mL). In patients with severe pancreatitis, serum concentrations of interleukin-6 were initially clearly elevated (35.0 + 7.5 U/mL) and remained slightly elevated until day 7 (13.0 + 2.0 U/mL). Patients with lethal outcome had markedly elevated initial interleukin-6 concentrations (61.0 + 15.0 U/mL) that decreased hut were still elevated at day 7 (26.0 + 2.5 U/mL). In all three groups, C-reactive protein concentrations followed the course of interleukin-6 concentrations by 1 day. There was a positive correlation between maximal interleukin 6 concentrations and maximal increases in the serum concentrations of C-reactive protein (r = 0.66). At days 1 and 2, increased ( > 15 U/mL) interleukin-6 concentrations (positive predictive value, 91%; negative predictive value, 82%) predicted a severe or lethal course of the disease more accurately than elevated [ > 0.10 g& (> 10 mg/dL)] C-reactive protein concentrations (positive predictive value, 67%; negative predictive value, 79%). In conclusion, elevated serum concentrations of interleukin-8 followed by increased levels of C-reactive protein reflect the severity of acute pancreatitis.
0
ne of the major clinical problems in acute pancreatitis is the early differentiation between mild and severe disease (1). Several prognostic indices have therefore been proposed to define high-risk patients (2-5). Recently, the prognostic value of increased serum concentrations of acute-phase proteins, particularly of C-reactive protein (CRP), has been emphasized (6-8). There is evidence, mainly from experimental studies, that the cytokine interleukin-6 (IL-6) induces the hepatic synthesis of CRP and other acute-phase proteins (9-11). On the background of these experimental findings, we have studied the following questions: Are measurable amounts of IL-6 released into the peripheral circulation during acute pancreatitis? Is there a correlation between the serum concentrations of IL-6 and CRP, i.e., is there evidence for an involvement of IL-6 in the induction of CRP synthesis in vivo? Do the serum concentrations of IL-6 reflect the severity of acute pancreatitis, i.e., is there evidence for an increased activation of the monocytel macrophage system in severe or lethal pancreatitis? Methods
Patients Fifty consecutive patients with acute pancreatitis admitted to the departments of internal medicine and
Abbreviations usedin thispaper: CRP, C-reactive protein; IL-8, interleukin-8. o 1991 by tbe American Gastroenterological Association 0018-5085/91/$3.00
IL-6 IN ACUTE PANCREATITIS
September 1991
surgery of the University of Freiburg over 14 months were studied. The diagnosis of acute pancreatitis was established by typical abdominal pain present not longer than 72 hours before hospitalization, accompanied by increased serum amylase levels (> 300 U/L; normal range, lo-100 UiL) and/or the typical appearance of acute pancreatitis in ultrasonography or computed tomography. Severity of pancreatitis was assessed by the number of complications occuring in each patient during the course of the disease (12). Pancreatitis was classified as mild (S 1 complication; n = 251, severe (2 2 complications; n = 15), or lethal (death due to pancreatitis
in hospital; n = 10).
Laboratory Methods The concentration of CRP [normal value, CO.008 giL determined immunologically in serum by laser nephelometry (Beckmann, Munich, Germany). For the determination of IL-6 concentration (13,14), the growth of an IL-6-dependent cell line (B9) was measured by counting [3H]thymidine incorporation into DNA (the B9 cell line was kindly provided by Dr. L. Aarden, Amsterdam, The Netherlands). From each patient, 100 FL serum was tested in serial dilutions. In all tests, a titration curve of recombinant human IL-6 (Fa. Boehringer Mannheim, Mannheim, Germany) was included. IL-6 activity resulting in half-maximal [3H]thymidine incorporation was defined as 1 U. The usable detection limit for IL-6 was 4 U/mL. ( < 0.8 mg/dL)] was
Data Analysis Data are expressed as mean + SEM. For IL-6 and CRP optimal predictive values (positive predictive value, percentage of patients with severe or lethal pancreatitis out of all patients with positive test results; negative predictive value, percentage of all patients with mild pancreatitis out of all patients with negative test results) for the presence of severe or lethal pancreatitis were calculated using receiver operator characteristics. Correlations between IL-6 and CRP levels were calculated by using linear regression grades and estimating the coefficient of correlation. Results Serum Concentrations Acute Pancreatitis
of Interleukin-6
During
Most of the patients with mild pancreatitis normal or only slightly elevated IL-6 concenat the beginning of the disease (22.0 + 9.8 U/mL). On the other hand, patients with severe (35.0 + 7.5 U/mL) or lethal (61.0 + 15.0 U/mL) disease initially had markedly enhanced IL-6 concentrations. With regard to the time course, patients with mild disease already had low IL-6 concentrations at day 4 (5.0 2 1.0 U/mL), whereas IL-6 levels in patients with severe or lethal disease decreased only slowly during the following days and remained enhanced at day 7 (13.0 + 2.0 U/mL in severe cases; 26.0 ? 2.5 U/mL in fatal cases). showed trations
Relationship Between Interleukin-6 C-Reactive Protein
783
and
Serum concentrations of CRP were differently elevated in patients with acute pancreatitis at day 1 [mild disease, 0.07 ? 0.01 g/L (6.6 -+ 1.4 mg/dL); severe disease, 0.15 ? 0.02 g/L (14.8 2 2.2 mg/dL); lethal outcome, 0.11 ? 0.03 g/L (10.9 + 3.1 mg/dL)]. During the following days, CRP concentrations further increased [up to 0.07 + 0.01 g/L (7.3 2 1.2 mg/ dL) at day 2 in mild disease; up to 0.17 * 0.02 g/L (17.0 5 1.8 mg/dL) at day 2 in severe disease; and up to 0.15 + 0.02 g/L (14.6 + 1.8 mg/dL) in fatal disease] and remained increased until day 7 in patients with severe [0.09 & 0.01 g/L (8.6 f 1.3 mg/dL)] or fatal [0.09 + 0.01 g/L (8.8 + 1.4 mg/dL)] disease. In all three groups of patients, the peaks of the mean values of CRP followed the peaks of the mean values of IL-6 by 1 day. When the time courses of the serum concentrations of IL-6 and CRP were analyzed in individual patients, the same relationships between IL-6 and CRP were found as for the mean values, i.e., peak concentrations of IL-6 preceded peak concentrations of CRP by about 1 day (Figure 1). When maximal serum concentrations of IL-6 at days l-5 were correlated with the maximal increases in the serum concentrations of CRP at days l-7 in all patients with acute pancreatitis, a linear relationship (r = 0.66) was found. Relationship Between Interleukin-6 Severity of Acute Pancreatitis
and
The sensitivity, specificity, positive predictive value, and negative predictive value of elevated (cut-off level, 15 U/mL) IL-6 serum concentrations for the early detection (days 1 and 2) of severe or lethal pancreatitis were 80%, 92%, 91%, and 82%, respectively. The corresponding values for elevated [> 0.01 g/L (> 10 mg/dL)] CRP levels were 83%, 62%, 67%, and 79%. It is evident that IL-6 is a better early parameter for the assessment of the severity of acute pancreatitis than CRP; only its sensitivity is lower than that of CRP. This might be due to the presence of patients whose serum IL-6 levels were elevated during the prehospitalization phase but were no longer elevated when they were admitted to the hospital. Discussion It has been proposed that in acute pancreatitis there is an activation of inflammatory cells resulting in the release of inflammatory mediators responsible for a severe course of the disease (15). In a previous report we have provided evidence for an activation of granulocytes in patients with severe or fatal acute pancreatitis (12). Granulocyte elastase was found to
784
LESER ET AL.
GASTROENTEROLOGY
Vol. 101, No. 3
Figure 1. Time course of IL-6 and C-reactive protein in individual patients with acute pancreatitis. 0, IL-6; A, CRP.
A. Male patient,
54 years old, with acute pancreatitis of undefined origin; mild disease.
B. Female patient, 48 years old, with acute pancreatitis in a pancreas divisum; severe disease.
0
2
4 dEYS
6
8
0
2
4
6
0
2
References Soergel KH. Acute pancreatitis. In: Sleisinger MH, Fordtran JS, eds. Gastrointestinal disease: pathophysiology, diagnosis, management. Philadelphia: Saunders, 1989:1814-1842. 2. Ranson JHC, Rifkind KM, Roses DF, Fink SD, Eng K, Spencer FC. Prognostic signs and the role of operative management in acute pancreatitis. Surg Gynecol Obstet 1974;139:69-80. 3. Imrie CW, Benjamin IS, Ferguson JC, McKay AJ, Mackenzie I, O’Neill J, Blumgart LH. A single centre double blind trial of trasylol therapy in primary acute pancreatitis. Br J Surg 1978;65:337-341. 4. Bank S, Wise L, Gersten M. Risk factors in acute pancreatitis. Am J Gastroenterol 1983;78:637-640.
4
6
0
d4YS
days
be a good and early marker for the assessment of the severity of the disease (12). In the present report we have studied the monokine IL-6, which is primarily released by activated mononuclear phagocytes and represents the key mediator for acute-phase protein synthesis in the liver (g-11). Until now there have been only a few in vivo studies showing elevation of serum IL-6 concentrations in humans. Thus far it has been shown that conditions such as severe burns (13), sepsis (16), major surgery (17), and renal graft rejection (14) lead to increased serum concentrations of IL-6. In the present study we show that measurable amounts of IL-6 are released into the circulation during acute pancreatitis. There is a close relationship in the amounts and the time courses of the serum concentrations of IL-6 and CRP, suggesting that during this inflammatory condition IL-6 is the main inducer of acute-phase protein synthesis in humans. High IL-6 levels are found in patients with a severe course of the disease and can therefore be used as a prognostic parameter. It can be assumed that high IL-6 levels reflect an increased activation of the monocyte/macrophage system in patients with severe acute pancreatitis, although other sites of synthesis, e.g., endothelial cells or fibroblasts, may contribute to the enhanced serum concentrations of IL-6.
I.
0
C. Female patient, 63 years old, with acute alcoholic pancreatitis; lethal disease.
5. Agarwal N, Pitchumoni CS. Simplified prognostic criteria in acute pancreatitis. Pancreas 1986;1:69-73. 6. Goodman AJ, Bird NC, Johnson AG. Antiprotease capacity in acute pancreatitis. Br J Surg 1986;73:796-798. 7. Btichler M, Malfertheiner P, Schoetensack C, Uhl W, Scherbaum W, Beger HG. Wertigkeit biochemischer und bildgebender Verfahren fur Diagnose und Prognose der akuten Pankreatitis. Z Gastroenterol1986;24:100-109. a. Puolakkainen P, Valtonen V, Paananen A, Schroder T. C-reactive protein (CRP) and serum phospholipase A, in the assessment of the severity of acute pancreatitis. Gut 1987;28:764771. C, Harnish D, Lansdorp P, Baumann H. 9. Gauldie J, Richards Interferon (3,/B-cell stimulatory factor type 2 shares identity with monocyte-derived hepatocyte stimulatory factor and regulates the major acute-phase protein response in liver cells. Proc Nat1 Acad Sci USA 1987;84:7251-7255. 10. Andus T, Geiger T, Hirano T, Northoff H, Ganter U, Bauer J, Kishimoto T, Heinrich PC. Recombinant human B cell stimulatory factor 2 (BSF-2/IFN-(32) regulates B-fibrinogen and albumin mRNA levels in Fao-9 cells. FEBS Lett 1987;221:18-22. MJ, David M, Hirano T, Kishimoto T, 11. Caste11 JV, Gomez-Lechon Heinrich
PC. Recombinant
human
interleukin-6
(IL-G/BSF-2/
HSF) regulates the synthesis of acute-phase proteins in human hepatocytes. FEBS Lett 1988;232:347-350. J, Leser H-G, Salm R, Lausen M, Ruck12. Gross V, Scholmerich auer K, Schoffel U, Lay L, Heinisch A, Farthmann EH, Gerok W. Granulocyte elastase in assessment of severity of acute pancreatitis. Comparison with acute-phase proteins C-reactive protein, cr,-antitrypsin, and protease inhibitor a,-macroglobulin. Dig Dis Sci 1990;35:97-105. 13. Nijsten MW, DeGroot ER, TenDuis HJ, Klesen HJ, Hack CE, Aarden LA. Serum levels of interleukin-6 and acute phase responses. Lancet i987;2:92i. 14. Van Oers MHJ, van der Heyden AAPAM, Aarden LA. Interleukin 6 (IL-6) in serum and urine of renal transplant recipients. Clin Exp Immunol1988;71:314-319. H. Fatal pancreatitis, a consequence of excessive 15. Rinderknecht leukocyte stimulation? Int J Pancreatol1988;3:105-112. P, Halstensen A, Kierulf P, Espevik T. 16. Waage A, Brandtzaeg The complex pattern of cytokines in serum from patients with meningococcal septic shock. Association between interleukin-6, interleukin-1, and fatal outcome. J Exp Med 1989;169: 333-338. N, Yoshizaki K, Tagoh H, Monden M, Kishimoto S, 17. Nishimoto Hirano T, Kishimoto T. Elevation of serum interleukin-6 prior
September
IL-6 IN ACUTE
1991
to acute operation.
phase proteins on the inflammation by surgical Clin Immunol Immunopathol 1989;50:399-401.
Received May 17, 1990. Accepted January 10,1991. Address requests for reprints to: Professor Jiirgen
Scholmerich,
PANCREATITIS
785
Medizinische Universitatsklinik, Hugstetter StraBe 55, D-7800 Freiburg, Germany. The authors thank G. Miiller-Buscher for her excellent technical assistance and G. Zahn and M. Ulrich for their help with the preparation of the manuscript. Dedicated to Professor Dr. W. Gerok on the occasion of his 65th birthday.
1991;101:782-785
Elevation of Serum Interleukin-6 Concentration Precedes Acute-Phase Response and Reflects Severity in Acute Pancreatitis H.-G. LESER, V. GROSS, C. SCHEIBENBOGEN, A. HEINISCH, R. SALM, M. LAUSEN, K. RtiCKAUER, R. ANDREESEN, E. H. FARTHMANN, and J. SCHhLMERICH Departments of Ehternal Medicine and Surgery, University of Freiburg, Freiburg, Germany
Experimental studies have shown that interleukin-6 induces all major acute-phase proteins in the liver, including C-reactive protein. In 50 patients with acute pancreatitis, the serum concentrations of interleukin-6 and C-reactive protein were determined daily during the first week of hospitalization. Patients were divided into three groups according to clinical criteria: mild pancreatitis [I 1 complication; (2 2 complications; n = 25), severe pancreatitis n = 15),and lethal outcome (n = 10). Patients with mild disease showed initially slightly elevated levels of interleukin-6 (22.0 + 9.8 WmL) that decreased to low levels within 4 days (5.0 k 1.0 U/mL). In patients with severe pancreatitis, serum concentrations of interleukin-6 were initially clearly elevated (35.0 + 7.5 U/mL) and remained slightly elevated until day 7 (13.0 + 2.0 U/mL). Patients with lethal outcome had markedly elevated initial interleukin-6 concentrations (61.0 + 15.0 U/mL) that decreased hut were still elevated at day 7 (26.0 + 2.5 U/mL). In all three groups, C-reactive protein concentrations followed the course of interleukin-6 concentrations by 1 day. There was a positive correlation between maximal interleukin 6 concentrations and maximal increases in the serum concentrations of C-reactive protein (r = 0.66). At days 1 and 2, increased ( > 15 U/mL) interleukin-6 concentrations (positive predictive value, 91%; negative predictive value, 82%) predicted a severe or lethal course of the disease more accurately than elevated [ > 0.10 g& (> 10 mg/dL)] C-reactive protein concentrations (positive predictive value, 67%; negative predictive value, 79%). In conclusion, elevated serum concentrations of interleukin-8 followed by increased levels of C-reactive protein reflect the severity of acute pancreatitis.
0
ne of the major clinical problems in acute pancreatitis is the early differentiation between mild and severe disease (1). Several prognostic indices have therefore been proposed to define high-risk patients (2-5). Recently, the prognostic value of increased serum concentrations of acute-phase proteins, particularly of C-reactive protein (CRP), has been emphasized (6-8). There is evidence, mainly from experimental studies, that the cytokine interleukin-6 (IL-6) induces the hepatic synthesis of CRP and other acute-phase proteins (9-11). On the background of these experimental findings, we have studied the following questions: Are measurable amounts of IL-6 released into the peripheral circulation during acute pancreatitis? Is there a correlation between the serum concentrations of IL-6 and CRP, i.e., is there evidence for an involvement of IL-6 in the induction of CRP synthesis in vivo? Do the serum concentrations of IL-6 reflect the severity of acute pancreatitis, i.e., is there evidence for an increased activation of the monocytel macrophage system in severe or lethal pancreatitis? Methods
Patients Fifty consecutive patients with acute pancreatitis admitted to the departments of internal medicine and
Abbreviations usedin thispaper: CRP, C-reactive protein; IL-8, interleukin-8. o 1991 by tbe American Gastroenterological Association 0018-5085/91/$3.00
IL-6 IN ACUTE PANCREATITIS
September 1991
surgery of the University of Freiburg over 14 months were studied. The diagnosis of acute pancreatitis was established by typical abdominal pain present not longer than 72 hours before hospitalization, accompanied by increased serum amylase levels (> 300 U/L; normal range, lo-100 UiL) and/or the typical appearance of acute pancreatitis in ultrasonography or computed tomography. Severity of pancreatitis was assessed by the number of complications occuring in each patient during the course of the disease (12). Pancreatitis was classified as mild (S 1 complication; n = 251, severe (2 2 complications; n = 15), or lethal (death due to pancreatitis
in hospital; n = 10).
Laboratory Methods The concentration of CRP [normal value, CO.008 giL determined immunologically in serum by laser nephelometry (Beckmann, Munich, Germany). For the determination of IL-6 concentration (13,14), the growth of an IL-6-dependent cell line (B9) was measured by counting [3H]thymidine incorporation into DNA (the B9 cell line was kindly provided by Dr. L. Aarden, Amsterdam, The Netherlands). From each patient, 100 FL serum was tested in serial dilutions. In all tests, a titration curve of recombinant human IL-6 (Fa. Boehringer Mannheim, Mannheim, Germany) was included. IL-6 activity resulting in half-maximal [3H]thymidine incorporation was defined as 1 U. The usable detection limit for IL-6 was 4 U/mL. ( < 0.8 mg/dL)] was
Data Analysis Data are expressed as mean + SEM. For IL-6 and CRP optimal predictive values (positive predictive value, percentage of patients with severe or lethal pancreatitis out of all patients with positive test results; negative predictive value, percentage of all patients with mild pancreatitis out of all patients with negative test results) for the presence of severe or lethal pancreatitis were calculated using receiver operator characteristics. Correlations between IL-6 and CRP levels were calculated by using linear regression grades and estimating the coefficient of correlation. Results Serum Concentrations Acute Pancreatitis
of Interleukin-6
During
Most of the patients with mild pancreatitis normal or only slightly elevated IL-6 concenat the beginning of the disease (22.0 + 9.8 U/mL). On the other hand, patients with severe (35.0 + 7.5 U/mL) or lethal (61.0 + 15.0 U/mL) disease initially had markedly enhanced IL-6 concentrations. With regard to the time course, patients with mild disease already had low IL-6 concentrations at day 4 (5.0 2 1.0 U/mL), whereas IL-6 levels in patients with severe or lethal disease decreased only slowly during the following days and remained enhanced at day 7 (13.0 + 2.0 U/mL in severe cases; 26.0 ? 2.5 U/mL in fatal cases). showed trations
Relationship Between Interleukin-6 C-Reactive Protein
783
and
Serum concentrations of CRP were differently elevated in patients with acute pancreatitis at day 1 [mild disease, 0.07 ? 0.01 g/L (6.6 -+ 1.4 mg/dL); severe disease, 0.15 ? 0.02 g/L (14.8 2 2.2 mg/dL); lethal outcome, 0.11 ? 0.03 g/L (10.9 + 3.1 mg/dL)]. During the following days, CRP concentrations further increased [up to 0.07 + 0.01 g/L (7.3 2 1.2 mg/ dL) at day 2 in mild disease; up to 0.17 * 0.02 g/L (17.0 5 1.8 mg/dL) at day 2 in severe disease; and up to 0.15 + 0.02 g/L (14.6 + 1.8 mg/dL) in fatal disease] and remained increased until day 7 in patients with severe [0.09 & 0.01 g/L (8.6 f 1.3 mg/dL)] or fatal [0.09 + 0.01 g/L (8.8 + 1.4 mg/dL)] disease. In all three groups of patients, the peaks of the mean values of CRP followed the peaks of the mean values of IL-6 by 1 day. When the time courses of the serum concentrations of IL-6 and CRP were analyzed in individual patients, the same relationships between IL-6 and CRP were found as for the mean values, i.e., peak concentrations of IL-6 preceded peak concentrations of CRP by about 1 day (Figure 1). When maximal serum concentrations of IL-6 at days l-5 were correlated with the maximal increases in the serum concentrations of CRP at days l-7 in all patients with acute pancreatitis, a linear relationship (r = 0.66) was found. Relationship Between Interleukin-6 Severity of Acute Pancreatitis
and
The sensitivity, specificity, positive predictive value, and negative predictive value of elevated (cut-off level, 15 U/mL) IL-6 serum concentrations for the early detection (days 1 and 2) of severe or lethal pancreatitis were 80%, 92%, 91%, and 82%, respectively. The corresponding values for elevated [> 0.01 g/L (> 10 mg/dL)] CRP levels were 83%, 62%, 67%, and 79%. It is evident that IL-6 is a better early parameter for the assessment of the severity of acute pancreatitis than CRP; only its sensitivity is lower than that of CRP. This might be due to the presence of patients whose serum IL-6 levels were elevated during the prehospitalization phase but were no longer elevated when they were admitted to the hospital. Discussion It has been proposed that in acute pancreatitis there is an activation of inflammatory cells resulting in the release of inflammatory mediators responsible for a severe course of the disease (15). In a previous report we have provided evidence for an activation of granulocytes in patients with severe or fatal acute pancreatitis (12). Granulocyte elastase was found to
784
LESER ET AL.
GASTROENTEROLOGY
Vol. 101, No. 3
Figure 1. Time course of IL-6 and C-reactive protein in individual patients with acute pancreatitis. 0, IL-6; A, CRP.
A. Male patient,
54 years old, with acute pancreatitis of undefined origin; mild disease.
B. Female patient, 48 years old, with acute pancreatitis in a pancreas divisum; severe disease.
0
2
4 dEYS
6
8
0
2
4
6
0
2
References Soergel KH. Acute pancreatitis. In: Sleisinger MH, Fordtran JS, eds. Gastrointestinal disease: pathophysiology, diagnosis, management. Philadelphia: Saunders, 1989:1814-1842. 2. Ranson JHC, Rifkind KM, Roses DF, Fink SD, Eng K, Spencer FC. Prognostic signs and the role of operative management in acute pancreatitis. Surg Gynecol Obstet 1974;139:69-80. 3. Imrie CW, Benjamin IS, Ferguson JC, McKay AJ, Mackenzie I, O’Neill J, Blumgart LH. A single centre double blind trial of trasylol therapy in primary acute pancreatitis. Br J Surg 1978;65:337-341. 4. Bank S, Wise L, Gersten M. Risk factors in acute pancreatitis. Am J Gastroenterol 1983;78:637-640.
4
6
0
d4YS
days
be a good and early marker for the assessment of the severity of the disease (12). In the present report we have studied the monokine IL-6, which is primarily released by activated mononuclear phagocytes and represents the key mediator for acute-phase protein synthesis in the liver (g-11). Until now there have been only a few in vivo studies showing elevation of serum IL-6 concentrations in humans. Thus far it has been shown that conditions such as severe burns (13), sepsis (16), major surgery (17), and renal graft rejection (14) lead to increased serum concentrations of IL-6. In the present study we show that measurable amounts of IL-6 are released into the circulation during acute pancreatitis. There is a close relationship in the amounts and the time courses of the serum concentrations of IL-6 and CRP, suggesting that during this inflammatory condition IL-6 is the main inducer of acute-phase protein synthesis in humans. High IL-6 levels are found in patients with a severe course of the disease and can therefore be used as a prognostic parameter. It can be assumed that high IL-6 levels reflect an increased activation of the monocyte/macrophage system in patients with severe acute pancreatitis, although other sites of synthesis, e.g., endothelial cells or fibroblasts, may contribute to the enhanced serum concentrations of IL-6.
I.
0
C. Female patient, 63 years old, with acute alcoholic pancreatitis; lethal disease.
5. Agarwal N, Pitchumoni CS. Simplified prognostic criteria in acute pancreatitis. Pancreas 1986;1:69-73. 6. Goodman AJ, Bird NC, Johnson AG. Antiprotease capacity in acute pancreatitis. Br J Surg 1986;73:796-798. 7. Btichler M, Malfertheiner P, Schoetensack C, Uhl W, Scherbaum W, Beger HG. Wertigkeit biochemischer und bildgebender Verfahren fur Diagnose und Prognose der akuten Pankreatitis. Z Gastroenterol1986;24:100-109. a. Puolakkainen P, Valtonen V, Paananen A, Schroder T. C-reactive protein (CRP) and serum phospholipase A, in the assessment of the severity of acute pancreatitis. Gut 1987;28:764771. C, Harnish D, Lansdorp P, Baumann H. 9. Gauldie J, Richards Interferon (3,/B-cell stimulatory factor type 2 shares identity with monocyte-derived hepatocyte stimulatory factor and regulates the major acute-phase protein response in liver cells. Proc Nat1 Acad Sci USA 1987;84:7251-7255. 10. Andus T, Geiger T, Hirano T, Northoff H, Ganter U, Bauer J, Kishimoto T, Heinrich PC. Recombinant human B cell stimulatory factor 2 (BSF-2/IFN-(32) regulates B-fibrinogen and albumin mRNA levels in Fao-9 cells. FEBS Lett 1987;221:18-22. MJ, David M, Hirano T, Kishimoto T, 11. Caste11 JV, Gomez-Lechon Heinrich
PC. Recombinant
human
interleukin-6
(IL-G/BSF-2/
HSF) regulates the synthesis of acute-phase proteins in human hepatocytes. FEBS Lett 1988;232:347-350. J, Leser H-G, Salm R, Lausen M, Ruck12. Gross V, Scholmerich auer K, Schoffel U, Lay L, Heinisch A, Farthmann EH, Gerok W. Granulocyte elastase in assessment of severity of acute pancreatitis. Comparison with acute-phase proteins C-reactive protein, cr,-antitrypsin, and protease inhibitor a,-macroglobulin. Dig Dis Sci 1990;35:97-105. 13. Nijsten MW, DeGroot ER, TenDuis HJ, Klesen HJ, Hack CE, Aarden LA. Serum levels of interleukin-6 and acute phase responses. Lancet i987;2:92i. 14. Van Oers MHJ, van der Heyden AAPAM, Aarden LA. Interleukin 6 (IL-6) in serum and urine of renal transplant recipients. Clin Exp Immunol1988;71:314-319. H. Fatal pancreatitis, a consequence of excessive 15. Rinderknecht leukocyte stimulation? Int J Pancreatol1988;3:105-112. P, Halstensen A, Kierulf P, Espevik T. 16. Waage A, Brandtzaeg The complex pattern of cytokines in serum from patients with meningococcal septic shock. Association between interleukin-6, interleukin-1, and fatal outcome. J Exp Med 1989;169: 333-338. N, Yoshizaki K, Tagoh H, Monden M, Kishimoto S, 17. Nishimoto Hirano T, Kishimoto T. Elevation of serum interleukin-6 prior
September
IL-6 IN ACUTE
1991
to acute operation.
phase proteins on the inflammation by surgical Clin Immunol Immunopathol 1989;50:399-401.
Received May 17, 1990. Accepted January 10,1991. Address requests for reprints to: Professor Jiirgen
Scholmerich,
PANCREATITIS
785
Medizinische Universitatsklinik, Hugstetter StraBe 55, D-7800 Freiburg, Germany. The authors thank G. Miiller-Buscher for her excellent technical assistance and G. Zahn and M. Ulrich for their help with the preparation of the manuscript. Dedicated to Professor Dr. W. Gerok on the occasion of his 65th birthday.