- Email: [email protected]
Cytokines and acute pancreatitis
February 1996
EDITORIALS 639
Cytokines and Acute Pancreatitis See article on page 583.
A
cute pancreatitis is a serious disease with causes that remain obscure and for which treatment is still largely supportive. The overall mortality rate is about 10%, but in its most severe form, which is characterized by pancreatic necrosis, 20%–30% of patients die. Those who survive necrotizing pancreatitis often do so after a prolonged hospitalization requiring intensive care and one or more major abdominal operations. The cause of death in most of these patients does not seem to be related specifically to the pancreatic inflammation or even to the infection of the necrotic pancreas or peripancreatic tissue that may occur. Rather, death is often the result of multiorgan system failure, which seems to be the same as the multiorgan system failure found in other seemingly unrelated conditions (e.g., sepsis, major trauma, burns). In addition to organ dysfunction, general derangements include hypovolemia, a hyperdynamic state, fluid loss from the intravascular space, and increased capillary permeability. Adult respiratory distress syndrome is common in these patients, and it cannot be distinguished clinically or histologically from adult respiratory distress syndrome associated with sepsis. In necrotizing pancreatitis, it can occur even in the absence of infection. The mechanism(s) by which the effects of pancreatic inflammation spread to involve distant organ systems is unclear, but evidence suggests that activated pancreatic macrophages may release inflammatory cytokines (e.g., interleukin [IL] 1, IL-6, and tumor necrosis factor [TNF] a) as a response to the local tissue damage. These cytokines would be expected to act locally to aggravate the pancreatitis and both locally and systemically to increase capillary permeability and promote leukocyte adherence and extravasation. Another important role of activated macrophages is the presentation of antigens to T lymphocytes and their subsequent activation. IL-1 is also a potent stimulus for the synthesis and release of IL-2 from T lymphocytes. These activities are responsible for the phenomenon of cell-mediated immunity. Thus, the local response could produce far-reaching effects throughout the body. In the report by Curley et al., the authors found evidence for impaired cell-mediated immunity (depressed production of IL-2) in a murine model of acute pancreatitis. They were able to stimulate IL-2 production in vitro, and exogenous IL-2 protected the animals against a subsequent endotoxin challenge.1 The observation is inter/ m4787$0048
01-17-96 14:19:44
gasa
esting and timely, because it focuses attention on our growing understanding of the roles of both macrophage and T-cell–derived cytokines in the inflammatory and immunologic changes during acute pancreatitis.
The Role of Macrophage-Derived Cytokines Inflammation The sequence of events leading to the activation of the cytokine cascade in the early phases of inflammation is not understood completely. However, because the initial stages of acute inflammation precede the recruitment of immune-specific T and B cells, macrophages are believed to be the most likely source of both proinflammatory (IL-1, IL-6, and TNF-a) and anti-inflammatory (IL-10 and IL-1ra) agents. These proinflammatory cytokines have been implicated in many inflammatory and immunologic responses evoked during infection or tissue injury. TNF-a and IL1 are endogenous pyrogens that also cause a number of metabolic disorders and immunologic responses in various cell types.2,3 Studies in patients and animal models of endotoxic shock suggest that TNF-a is an important mediator of the systemic effects of sepsis.4 IL-6 is a principal inducer of the synthesis of hepatic acute phase proteins.5 IL-8, another cytokine produced mainly by the macrophage and endothelial cell, has been shown to be important in neutrophil activation. These inflammatory cytokines also induce expression of cell adhesion molecules (e.g., intercellular adhesion molecule) on vascular endothelial cells and cause leukocyte adhesion.6 IL-10 has been identified as a major anti-inflammatory cytokine also released by the macrophage. It inhibits the secretion of proinflammatory cytokines by monocytes, macrophages, and Th1 cells.7 In a study by Bean et al., IL-10 was found to protect mice against lethal shock induced by staphylococcal enterotoxin B.8 Protection was apparent when IL-10 was given either before or at the same time as staphylococcal enterotoxin B. IL-10 was less effective when it was administered after staphylococcal enterotoxin B injection. This was interpreted to mean that IL-10 was capable of regulating T-cell activation in vivo. Acute Pancreatitis Evidence is accumulating that a very early event in the evolution of acute pancreatitis is the release of endogenous inflammatory mediators from the inflamed WBS-Gastro
640 EDITORIALS
GASTROENTEROLOGY Vol. 110, No. 2
pancreas. Norman et al. found that experimental pancreatitis was associated with the release of IL-1, IL-6, and TNF-a into the serum within an hour of onset of the pancreatic insult. The serum levels of these cytokines correlated well with the degree of pancreatic inflammation, and their source was shown to be the inflamed pancreas.9 Heath et al. showed that serum levels of IL6 from patients with acute pancreatitis correlated with the severity of the disease.10 Viedma et al. found that IL-6 levels correlated well with C-reactive protein and phospholipase A activity, two other markers of disease severity.11 This suggested a causal role for IL-6 in the acute-phase response. Grewal et al. showed recently that IL-1, IL-6, and TNF-a levels were all elevated in the serum of animals with acute pancreatitis.12 TNF levels were also elevated in rats with acute pancreatitis, and this elevation was independent of the presence of endotoxin. Pretreatment with anti-TNF antibodies attenuated the expected increase of serum TNF, glucose, and amylase levels.13 Guice et al. also found high levels of serum TNFa in a model of cerulein pancreatitis. In their experience, pretreatment with anti-TNF antibodies seemed to worsen the pancreatitis and increased pulmonary vasculature leakage.14 The explanation for this finding remains largely speculative. Gross et al. has shown that IL-8 contributed to the early neutrophil activation during acute pancreatitis and the subsequent release of neutrophil elastase. He further showed that circulating levels of neutrophil elastase correlated with the severity of acute pancreatitis.15 Because IL-8 is produced mainly by monocytes and endothelial cells, two possibilities could explain the recruitment of neutrophils to the inflamed pancreas and their subsequent activation. The resident activated macrophages might be the source of the IL-8. Alternatively, histamine and related proteins might be released into the interstitial space during the early inflammatory response; these could activate the endothelial cells. IL-8 and platelet activating factor (PAF) might then be released from the vascular endothelium, and recruitment of neutrophils could follow. Indeed, there is much evidence that PAF may also be important in the pathogenesis of acute pancreatitis. This low-molecular-weight phospholipid is responsible for a number of noxious effects, including platelet, macrophage, and neutrophil aggregation; hypotension; and capillary leakage.16,17 There are several recent reports suggesting the clinical efficacy of a PAF antagonist in the treatment of acute pancreatitis. The effects of the anti-inflammatory cytokines on the tissue damage associated with pancreatitis are now being studied. Van Laethem et al. pretreated animals with IL10, which decreased the severity of subsequent experi/ m4787$0048
01-17-96 14:19:44
gasa
mental acute pancreatitis. The IL-10 seemed to retard the development of acinar necrosis, which they believed was due to the inhibition of release of TNF-a from the inflamed pancreas.18 We have shown that IL-10 reduced the severity of the pancreatitis even when it was administered after the inflammation was induced. In rats with cerulein pancreatitis, IL-10 improved the histological features and lowered the serum enzyme levels.19 In the choline-deficient, ethionine-supplemented diet model of pancreatitis in mice, we also found that treatment with IL-10 lessened the severity of established pancreatitis and lowered the mortality rate.20 The IL-10 administration significantly lowered the serum levels of IL-6, TNF-a, and IL-1b, suggesting their importance in promoting the early inflammatory reaction.
The Role of T-Cell–Derived Cytokines Inflammation Cell-mediated immunity and humoral immune responses are regulated by different sets of cytokines secreted by lymphocytes called T-helper cells. It is well known that the macrophage, through the major histocompatibility complex II, binds, activates, and subsequently recruits the CD4-positive, T-helper lymphocytes. In addition, macrophages secrete IL-1 in response to foreign antigens, including bacteria and their products, particularly endotoxin.3 IL-1 is known to be a very potent stimulus for the synthesis and release of IL-2 from T lymphocytes.21 Thus, the subsequent release of T-helper cytokines (e.g., IL-2, IFN-g) propagates the inflammatory response. The role of the cytokine IL-2, which arises primarily from CD4-positive T-helper lymphocytes, has long been recognized as central to normal immunologic function.22 Recent studies showed the appearance of IL-2 surface receptors on activated monocytes, implicating the Thelper cell/IL-2 macrophage interaction as an important part of the immunoregulatory cascade. An impairment of immune function occurs with a decrease in the proportion of T-helper lymphocytes in the peripheral blood, lowered production of IL-2, or a decrease in T cell proliferation. One or more of these have been shown recently in patients with burns, trauma, or acute pancreatitis, and their magnitude correlated with the incidence of disease severity, sepsis, and survival.23 – 25 Acute Pancreatitis The degree to which cellular immune function is disturbed in acute pancreatitis remains unclear, but the foregoing review suggests that some abnormalities do occur. We recently studied the effects of experimental WBS-Gastro
February 1996
EDITORIALS 641
acute pancreatitis on the likelihood of pancreatic infection in cats.26 We found that pancreatitis reduced the rate of clearance of Escherichia coli from the circulation by 28% and concluded that this was due to impaired systemic phagocytic function caused by the pancreatic inflammation. We also investigated the ability of the immunostimulant levamisole to reverse the abnormalities in immune function. When pancreatitis was present, the incidence of pancreatic infection was 73%. Levamisole reduced the rate of infection to 22%. The mechanism by which this occurred was not clarified, but it is known that levamisole improves immune function by enhancing the function of lymphocytes and macrophages. It also potentiates IL-2 and enhances random migration and phagocytosis by leukocytes and macrophages. Thus, those observations are consistent with those of Curley et al. in this issue of GASTROENTEROLOGY.
Implications of Macrophage and T-Cell Interactions in Acute Pancreatitis As information accumulates about the interactive role of macrophages and T cells in inflammatory conditions and their local and systemic effects, the logic of a new strategy for the treatment of acute pancreatitis becomes apparent. The evidence seems clear that the early response to pancreatic inflammation involves predominantly the tissue macrophages in and around the pancreas. A variety of proinflammatory mediators are released (i.e., cytokines, prostanoids, PAF, complement, etc.) whose initial job seems to be to limit the local damage. On the other hand, data from animal experiments suggest that these mediators themselves can exacerbate the severity of the pancreatitis when they continue to be elaborated in greater amounts or for longer periods. When their actions are blocked or their release is inhibited, the severity of the pancreatitis and its associated mortality is less. This suggests the possibility that early in the clinical course of pancreatitis, agents that inhibit the release and/or action of these agents could be beneficial. Obvious examples include PAF antagonists, which are already being tested in clinical trials, and IL-10, which seems promising in animal studies. Later in the course of the disease, the role of the cellular immune system may be more important in determining outcome. This does not imply that an intact immune system is important only to resist pancreatic infection. As Curley et al. have pointed out, endotoxin itself (without infection) increases the mortality rate in experimental pancreatitis when the immune system is impaired. Restoration of immune function protected against the effects / m4787$0048
01-17-96 14:19:44
gasa
of endotoxin, which include multiorgan system failure. Finally, it is known that bacterial translocation (probably from the colon) and endotoxemia occur in many patients with necrotizing pancreatitis. Thus, it seems logical to consider treatment of patients later in the course of pancreatitis with immunostimulatory agents that could overcome any deficiency in immune function. Examples include levamisole,26 glucan,27 and IL-2 or related substances. It is obvious that our incomplete understanding of the complex interactions between the macrophages and T cells and their numerous secretory products makes the foregoing analysis a gross oversimplification. Nevertheless, there seems to be some room for optimism with this new approach, which views pancreatitis like other major insults (e.g., burns, trauma, sepsis) in terms of the systemic response that they all provoke. It makes sense that the treatment should be directed toward a modification of that response. AMY M. KUSSKE ANTHONY J. RONGIONE HOWARD A. REBER
UCLA Center for the Health Sciences and Sepulveda VA Medical Center Sepulveda, California
References 1. Curley P, Nestor M, Collins K, Saporoschetz I, Mendez M, Mannick JA, Rodrick ML. Decreased interleukin-2 production in murine acute pancreatitis: potential for immunomodulation. Gastroenterology 1996;110:583–588. 2. Old LJ. Tumor necrosis factor. Science 1985;230:630. 3. Dinarello CA. Human pyrogen: a monocyte product mediating host defenses. In: Gallin JI, Fauci AS, eds. Advances in host defense mechanisms. Volume 1. Phagocytic cells. New York: Raven, 1982:57–74. 4. Tracey KJ, Beutler B, Lowry SF, Merryweather J, Wolpe S, Milsark IW, Hariri RJ, Fahey T III, Zentella A, Albert JD, Shires GT, Cerami A. Shock and tissue injury induced by recombinant human cahectin. Science 1986;234:470–474. 5. Hirano T, Taga T, Yamasaki K, Matsuda T. A multifunctional cytokine (IL-6/BSF-2) and its receptor. Int Arch Allergy Appl Immunol 1989;88:29. 6. Springer TA. Adhesion receptors of the immune system. Nature 1990;346:425–434. 7. Fiorentino D, Zlotnik A, Mosmann T, Howard M, O’Garra A. IL-10 inhibits cytokine production by activated macrophages. J Immunol 1991;147:3815–3822. 8. Bean AGD, Freiberg RA, Andrade S, Menon S, Zlotnik A. Interleukin 10 protects mice against Staphylococcal Enterotoxin B-induced lethal shock. Infect Immun 1993;61:4937–4939. 9. Norman J, Franz M, Messina J, Riker A, Fabri PJ, Rosemurgy AS, Gower WR. Interleukin-1 receptor antagonist decreases severity of experimental acute pancreatitis. Surgery 1994;117:648– 655. 10. Heath DL, Cruickshank DH, Gudgeon M, Jehanli A, Shenkin A, Imrie CW. Role of interleukin-6 in mediating the acute phase protein response and potential as an early means of severity assessment in acute pancreatitis. Pancreas 1993;66:41–45. 11. Viedma JA, Perez-Mateo M, Dominguez JE, Carballo F. Role of
WBS-Gastro
642 EDITORIALS
12.
13.
14.
15.
16. 17.
18.
19.
20.
GASTROENTEROLOGY Vol. 110, No. 2
interleukin-6 in acute pancreatitis. Comparison with C-reactive protein and phospholipase A. Gut 1992;33:1264–1267. Grewal HP, Malak K, El Din AM, Ohman M, Salem A, Gabor L, Gabor AO. Induction of tumor necrosis factor in severe acute pancreatitis and its subsequent reduction after hepatic passage. Surgery 1994;115:213–221. Grewal HP, Mohey EDA, Gaber L, Kotb M, Gaber A. Amelioration of the physiologic and biochemical changes of acute pancreatitis using an anti-TNF-alpha polyclonal antibody. Am J Surg 1994;167:214–219. Guice KS, Oldham KT, Remick DG, Kunkel SL, Ward PA. Antitumor necrosis factor antibody augments edema formation in cerulein-induced acute pancreatitis. J Surg Res 1991;51:495– 499. Gross V, Andreesen R, Leser H-G, Ceska M, Liehl E, Lausen M, Farthmann EH, Scholmerich J. Interleukin-8 and neutrophil activation in acute pancreatitis. Eur J Clin Invest 1992;22:200– 203. Hahahan DJ. Platelet activating factor: a biologically active phosphoglyceride. Ann Rev Biochem 1986;35:493–509. Camussi G, Tetta C, Bussolino F, Caligaris-Cappio F, Masera C, Segoloni G. Mediators of immune complex induced aggregation of polymorphonuclear neutrophils. II. Platelet-activating factor as the effector substance of immune-induced aggregation. Int Arch Allergy Appl Immunol 1981;64:25–41. Van Laethem JV, Marchant A, Delvaux A, Goldman M, Robberecht P, Velu T, Deviere J. Interleukin 10 prevents necrosis in murine experimental pancreatitis. Gastroenterology 1995;108:1917– 1922. Rongione AJ, Kusske AM, Ashley SW, Reber HA, McFadden DW. Interleukin 10 reduces severity of acute pancreatitis in the rat (abstr). Pancreas 1995;11:446. Kusske AM, Rongione AJ, Ashley SW, McFadden DW, Reber HA.
/ m4787$0048
01-17-96 14:19:44
gasa
21.
22.
23.
24.
25.
26.
27.
Interleukin 10 (IL-10) prevents death in lethal necrotizing pancreatitis (AP) in mice (abstr). Surgery (in press). Smith KA, Lachman LB, Oppenheim JJ, Favata MF. The functional relationship of the Interleukins. J Exp Med 1980;151:1551– 1556. Mosmann TR, Coffman RL. Th1 and TH2 cells: different patterns of lymphokine secretion lead to different functional properties. Ann Rev Immunol 1989;7:145–173. Wood J, Rodrick ML, O’Mahoney JB, Palder SB, Saporoschetz I, D’eon P, Mannick JA. Inadequate interleukin 2 production: a fundamental immunological deficiency in patients with major burns. Ann Surg 1984;200:311–320. Teodorczyk-Injeyan JA, McRitchie DI, Peters WJ. Expression and secretion of IL-2 receptor in trauma patients. Ann Surg 1990; 212:202–208. Curley PJ, McMahon MJ, Lancaster F, Banks RE, Barclay GR, Shefta J, Boylston AW, Whicher JT. Reduction in circulating levels of CD4-positive lymphocytes in acute pancreatitis: relationship to endotoxin, interleukin 6 and disease severity. Br J Surg 1993;80:1312–1315. Widdison AL, Karanjia ND, Alvarez C, Reber HA. Reticuloendothelial function, and efficacy of levamisole for the treatment of pancreatic infection in acute necrotizing pancreatitis. Am J Surg 1992;163:100–104. Browder IW, Sherwood E, Williams D, Jones E, McNamee R, DiLuzio N. Protective effects of glucan-enhanced macrophage function in experimental pancreatitis. Am J Surg 1987;153:25– 33.
Address requests for reprints to: Howard A. Reber, M.D., Department of Surgery, Sepulveda VA Medical Center, 16111 Plummer Street, Building 2, Sepulveda, California 91343. Fax: (818) 8959421. 䉷 1996 by the American Gastroenterological Association 0016-5085/96/$3.00
WBS-Gastro
EDITORIALS 639
Cytokines and Acute Pancreatitis See article on page 583.
A
cute pancreatitis is a serious disease with causes that remain obscure and for which treatment is still largely supportive. The overall mortality rate is about 10%, but in its most severe form, which is characterized by pancreatic necrosis, 20%–30% of patients die. Those who survive necrotizing pancreatitis often do so after a prolonged hospitalization requiring intensive care and one or more major abdominal operations. The cause of death in most of these patients does not seem to be related specifically to the pancreatic inflammation or even to the infection of the necrotic pancreas or peripancreatic tissue that may occur. Rather, death is often the result of multiorgan system failure, which seems to be the same as the multiorgan system failure found in other seemingly unrelated conditions (e.g., sepsis, major trauma, burns). In addition to organ dysfunction, general derangements include hypovolemia, a hyperdynamic state, fluid loss from the intravascular space, and increased capillary permeability. Adult respiratory distress syndrome is common in these patients, and it cannot be distinguished clinically or histologically from adult respiratory distress syndrome associated with sepsis. In necrotizing pancreatitis, it can occur even in the absence of infection. The mechanism(s) by which the effects of pancreatic inflammation spread to involve distant organ systems is unclear, but evidence suggests that activated pancreatic macrophages may release inflammatory cytokines (e.g., interleukin [IL] 1, IL-6, and tumor necrosis factor [TNF] a) as a response to the local tissue damage. These cytokines would be expected to act locally to aggravate the pancreatitis and both locally and systemically to increase capillary permeability and promote leukocyte adherence and extravasation. Another important role of activated macrophages is the presentation of antigens to T lymphocytes and their subsequent activation. IL-1 is also a potent stimulus for the synthesis and release of IL-2 from T lymphocytes. These activities are responsible for the phenomenon of cell-mediated immunity. Thus, the local response could produce far-reaching effects throughout the body. In the report by Curley et al., the authors found evidence for impaired cell-mediated immunity (depressed production of IL-2) in a murine model of acute pancreatitis. They were able to stimulate IL-2 production in vitro, and exogenous IL-2 protected the animals against a subsequent endotoxin challenge.1 The observation is inter/ m4787$0048
01-17-96 14:19:44
gasa
esting and timely, because it focuses attention on our growing understanding of the roles of both macrophage and T-cell–derived cytokines in the inflammatory and immunologic changes during acute pancreatitis.
The Role of Macrophage-Derived Cytokines Inflammation The sequence of events leading to the activation of the cytokine cascade in the early phases of inflammation is not understood completely. However, because the initial stages of acute inflammation precede the recruitment of immune-specific T and B cells, macrophages are believed to be the most likely source of both proinflammatory (IL-1, IL-6, and TNF-a) and anti-inflammatory (IL-10 and IL-1ra) agents. These proinflammatory cytokines have been implicated in many inflammatory and immunologic responses evoked during infection or tissue injury. TNF-a and IL1 are endogenous pyrogens that also cause a number of metabolic disorders and immunologic responses in various cell types.2,3 Studies in patients and animal models of endotoxic shock suggest that TNF-a is an important mediator of the systemic effects of sepsis.4 IL-6 is a principal inducer of the synthesis of hepatic acute phase proteins.5 IL-8, another cytokine produced mainly by the macrophage and endothelial cell, has been shown to be important in neutrophil activation. These inflammatory cytokines also induce expression of cell adhesion molecules (e.g., intercellular adhesion molecule) on vascular endothelial cells and cause leukocyte adhesion.6 IL-10 has been identified as a major anti-inflammatory cytokine also released by the macrophage. It inhibits the secretion of proinflammatory cytokines by monocytes, macrophages, and Th1 cells.7 In a study by Bean et al., IL-10 was found to protect mice against lethal shock induced by staphylococcal enterotoxin B.8 Protection was apparent when IL-10 was given either before or at the same time as staphylococcal enterotoxin B. IL-10 was less effective when it was administered after staphylococcal enterotoxin B injection. This was interpreted to mean that IL-10 was capable of regulating T-cell activation in vivo. Acute Pancreatitis Evidence is accumulating that a very early event in the evolution of acute pancreatitis is the release of endogenous inflammatory mediators from the inflamed WBS-Gastro
640 EDITORIALS
GASTROENTEROLOGY Vol. 110, No. 2
pancreas. Norman et al. found that experimental pancreatitis was associated with the release of IL-1, IL-6, and TNF-a into the serum within an hour of onset of the pancreatic insult. The serum levels of these cytokines correlated well with the degree of pancreatic inflammation, and their source was shown to be the inflamed pancreas.9 Heath et al. showed that serum levels of IL6 from patients with acute pancreatitis correlated with the severity of the disease.10 Viedma et al. found that IL-6 levels correlated well with C-reactive protein and phospholipase A activity, two other markers of disease severity.11 This suggested a causal role for IL-6 in the acute-phase response. Grewal et al. showed recently that IL-1, IL-6, and TNF-a levels were all elevated in the serum of animals with acute pancreatitis.12 TNF levels were also elevated in rats with acute pancreatitis, and this elevation was independent of the presence of endotoxin. Pretreatment with anti-TNF antibodies attenuated the expected increase of serum TNF, glucose, and amylase levels.13 Guice et al. also found high levels of serum TNFa in a model of cerulein pancreatitis. In their experience, pretreatment with anti-TNF antibodies seemed to worsen the pancreatitis and increased pulmonary vasculature leakage.14 The explanation for this finding remains largely speculative. Gross et al. has shown that IL-8 contributed to the early neutrophil activation during acute pancreatitis and the subsequent release of neutrophil elastase. He further showed that circulating levels of neutrophil elastase correlated with the severity of acute pancreatitis.15 Because IL-8 is produced mainly by monocytes and endothelial cells, two possibilities could explain the recruitment of neutrophils to the inflamed pancreas and their subsequent activation. The resident activated macrophages might be the source of the IL-8. Alternatively, histamine and related proteins might be released into the interstitial space during the early inflammatory response; these could activate the endothelial cells. IL-8 and platelet activating factor (PAF) might then be released from the vascular endothelium, and recruitment of neutrophils could follow. Indeed, there is much evidence that PAF may also be important in the pathogenesis of acute pancreatitis. This low-molecular-weight phospholipid is responsible for a number of noxious effects, including platelet, macrophage, and neutrophil aggregation; hypotension; and capillary leakage.16,17 There are several recent reports suggesting the clinical efficacy of a PAF antagonist in the treatment of acute pancreatitis. The effects of the anti-inflammatory cytokines on the tissue damage associated with pancreatitis are now being studied. Van Laethem et al. pretreated animals with IL10, which decreased the severity of subsequent experi/ m4787$0048
01-17-96 14:19:44
gasa
mental acute pancreatitis. The IL-10 seemed to retard the development of acinar necrosis, which they believed was due to the inhibition of release of TNF-a from the inflamed pancreas.18 We have shown that IL-10 reduced the severity of the pancreatitis even when it was administered after the inflammation was induced. In rats with cerulein pancreatitis, IL-10 improved the histological features and lowered the serum enzyme levels.19 In the choline-deficient, ethionine-supplemented diet model of pancreatitis in mice, we also found that treatment with IL-10 lessened the severity of established pancreatitis and lowered the mortality rate.20 The IL-10 administration significantly lowered the serum levels of IL-6, TNF-a, and IL-1b, suggesting their importance in promoting the early inflammatory reaction.
The Role of T-Cell–Derived Cytokines Inflammation Cell-mediated immunity and humoral immune responses are regulated by different sets of cytokines secreted by lymphocytes called T-helper cells. It is well known that the macrophage, through the major histocompatibility complex II, binds, activates, and subsequently recruits the CD4-positive, T-helper lymphocytes. In addition, macrophages secrete IL-1 in response to foreign antigens, including bacteria and their products, particularly endotoxin.3 IL-1 is known to be a very potent stimulus for the synthesis and release of IL-2 from T lymphocytes.21 Thus, the subsequent release of T-helper cytokines (e.g., IL-2, IFN-g) propagates the inflammatory response. The role of the cytokine IL-2, which arises primarily from CD4-positive T-helper lymphocytes, has long been recognized as central to normal immunologic function.22 Recent studies showed the appearance of IL-2 surface receptors on activated monocytes, implicating the Thelper cell/IL-2 macrophage interaction as an important part of the immunoregulatory cascade. An impairment of immune function occurs with a decrease in the proportion of T-helper lymphocytes in the peripheral blood, lowered production of IL-2, or a decrease in T cell proliferation. One or more of these have been shown recently in patients with burns, trauma, or acute pancreatitis, and their magnitude correlated with the incidence of disease severity, sepsis, and survival.23 – 25 Acute Pancreatitis The degree to which cellular immune function is disturbed in acute pancreatitis remains unclear, but the foregoing review suggests that some abnormalities do occur. We recently studied the effects of experimental WBS-Gastro
February 1996
EDITORIALS 641
acute pancreatitis on the likelihood of pancreatic infection in cats.26 We found that pancreatitis reduced the rate of clearance of Escherichia coli from the circulation by 28% and concluded that this was due to impaired systemic phagocytic function caused by the pancreatic inflammation. We also investigated the ability of the immunostimulant levamisole to reverse the abnormalities in immune function. When pancreatitis was present, the incidence of pancreatic infection was 73%. Levamisole reduced the rate of infection to 22%. The mechanism by which this occurred was not clarified, but it is known that levamisole improves immune function by enhancing the function of lymphocytes and macrophages. It also potentiates IL-2 and enhances random migration and phagocytosis by leukocytes and macrophages. Thus, those observations are consistent with those of Curley et al. in this issue of GASTROENTEROLOGY.
Implications of Macrophage and T-Cell Interactions in Acute Pancreatitis As information accumulates about the interactive role of macrophages and T cells in inflammatory conditions and their local and systemic effects, the logic of a new strategy for the treatment of acute pancreatitis becomes apparent. The evidence seems clear that the early response to pancreatic inflammation involves predominantly the tissue macrophages in and around the pancreas. A variety of proinflammatory mediators are released (i.e., cytokines, prostanoids, PAF, complement, etc.) whose initial job seems to be to limit the local damage. On the other hand, data from animal experiments suggest that these mediators themselves can exacerbate the severity of the pancreatitis when they continue to be elaborated in greater amounts or for longer periods. When their actions are blocked or their release is inhibited, the severity of the pancreatitis and its associated mortality is less. This suggests the possibility that early in the clinical course of pancreatitis, agents that inhibit the release and/or action of these agents could be beneficial. Obvious examples include PAF antagonists, which are already being tested in clinical trials, and IL-10, which seems promising in animal studies. Later in the course of the disease, the role of the cellular immune system may be more important in determining outcome. This does not imply that an intact immune system is important only to resist pancreatic infection. As Curley et al. have pointed out, endotoxin itself (without infection) increases the mortality rate in experimental pancreatitis when the immune system is impaired. Restoration of immune function protected against the effects / m4787$0048
01-17-96 14:19:44
gasa
of endotoxin, which include multiorgan system failure. Finally, it is known that bacterial translocation (probably from the colon) and endotoxemia occur in many patients with necrotizing pancreatitis. Thus, it seems logical to consider treatment of patients later in the course of pancreatitis with immunostimulatory agents that could overcome any deficiency in immune function. Examples include levamisole,26 glucan,27 and IL-2 or related substances. It is obvious that our incomplete understanding of the complex interactions between the macrophages and T cells and their numerous secretory products makes the foregoing analysis a gross oversimplification. Nevertheless, there seems to be some room for optimism with this new approach, which views pancreatitis like other major insults (e.g., burns, trauma, sepsis) in terms of the systemic response that they all provoke. It makes sense that the treatment should be directed toward a modification of that response. AMY M. KUSSKE ANTHONY J. RONGIONE HOWARD A. REBER
UCLA Center for the Health Sciences and Sepulveda VA Medical Center Sepulveda, California
References 1. Curley P, Nestor M, Collins K, Saporoschetz I, Mendez M, Mannick JA, Rodrick ML. Decreased interleukin-2 production in murine acute pancreatitis: potential for immunomodulation. Gastroenterology 1996;110:583–588. 2. Old LJ. Tumor necrosis factor. Science 1985;230:630. 3. Dinarello CA. Human pyrogen: a monocyte product mediating host defenses. In: Gallin JI, Fauci AS, eds. Advances in host defense mechanisms. Volume 1. Phagocytic cells. New York: Raven, 1982:57–74. 4. Tracey KJ, Beutler B, Lowry SF, Merryweather J, Wolpe S, Milsark IW, Hariri RJ, Fahey T III, Zentella A, Albert JD, Shires GT, Cerami A. Shock and tissue injury induced by recombinant human cahectin. Science 1986;234:470–474. 5. Hirano T, Taga T, Yamasaki K, Matsuda T. A multifunctional cytokine (IL-6/BSF-2) and its receptor. Int Arch Allergy Appl Immunol 1989;88:29. 6. Springer TA. Adhesion receptors of the immune system. Nature 1990;346:425–434. 7. Fiorentino D, Zlotnik A, Mosmann T, Howard M, O’Garra A. IL-10 inhibits cytokine production by activated macrophages. J Immunol 1991;147:3815–3822. 8. Bean AGD, Freiberg RA, Andrade S, Menon S, Zlotnik A. Interleukin 10 protects mice against Staphylococcal Enterotoxin B-induced lethal shock. Infect Immun 1993;61:4937–4939. 9. Norman J, Franz M, Messina J, Riker A, Fabri PJ, Rosemurgy AS, Gower WR. Interleukin-1 receptor antagonist decreases severity of experimental acute pancreatitis. Surgery 1994;117:648– 655. 10. Heath DL, Cruickshank DH, Gudgeon M, Jehanli A, Shenkin A, Imrie CW. Role of interleukin-6 in mediating the acute phase protein response and potential as an early means of severity assessment in acute pancreatitis. Pancreas 1993;66:41–45. 11. Viedma JA, Perez-Mateo M, Dominguez JE, Carballo F. Role of
WBS-Gastro
642 EDITORIALS
12.
13.
14.
15.
16. 17.
18.
19.
20.
GASTROENTEROLOGY Vol. 110, No. 2
interleukin-6 in acute pancreatitis. Comparison with C-reactive protein and phospholipase A. Gut 1992;33:1264–1267. Grewal HP, Malak K, El Din AM, Ohman M, Salem A, Gabor L, Gabor AO. Induction of tumor necrosis factor in severe acute pancreatitis and its subsequent reduction after hepatic passage. Surgery 1994;115:213–221. Grewal HP, Mohey EDA, Gaber L, Kotb M, Gaber A. Amelioration of the physiologic and biochemical changes of acute pancreatitis using an anti-TNF-alpha polyclonal antibody. Am J Surg 1994;167:214–219. Guice KS, Oldham KT, Remick DG, Kunkel SL, Ward PA. Antitumor necrosis factor antibody augments edema formation in cerulein-induced acute pancreatitis. J Surg Res 1991;51:495– 499. Gross V, Andreesen R, Leser H-G, Ceska M, Liehl E, Lausen M, Farthmann EH, Scholmerich J. Interleukin-8 and neutrophil activation in acute pancreatitis. Eur J Clin Invest 1992;22:200– 203. Hahahan DJ. Platelet activating factor: a biologically active phosphoglyceride. Ann Rev Biochem 1986;35:493–509. Camussi G, Tetta C, Bussolino F, Caligaris-Cappio F, Masera C, Segoloni G. Mediators of immune complex induced aggregation of polymorphonuclear neutrophils. II. Platelet-activating factor as the effector substance of immune-induced aggregation. Int Arch Allergy Appl Immunol 1981;64:25–41. Van Laethem JV, Marchant A, Delvaux A, Goldman M, Robberecht P, Velu T, Deviere J. Interleukin 10 prevents necrosis in murine experimental pancreatitis. Gastroenterology 1995;108:1917– 1922. Rongione AJ, Kusske AM, Ashley SW, Reber HA, McFadden DW. Interleukin 10 reduces severity of acute pancreatitis in the rat (abstr). Pancreas 1995;11:446. Kusske AM, Rongione AJ, Ashley SW, McFadden DW, Reber HA.
/ m4787$0048
01-17-96 14:19:44
gasa
21.
22.
23.
24.
25.
26.
27.
Interleukin 10 (IL-10) prevents death in lethal necrotizing pancreatitis (AP) in mice (abstr). Surgery (in press). Smith KA, Lachman LB, Oppenheim JJ, Favata MF. The functional relationship of the Interleukins. J Exp Med 1980;151:1551– 1556. Mosmann TR, Coffman RL. Th1 and TH2 cells: different patterns of lymphokine secretion lead to different functional properties. Ann Rev Immunol 1989;7:145–173. Wood J, Rodrick ML, O’Mahoney JB, Palder SB, Saporoschetz I, D’eon P, Mannick JA. Inadequate interleukin 2 production: a fundamental immunological deficiency in patients with major burns. Ann Surg 1984;200:311–320. Teodorczyk-Injeyan JA, McRitchie DI, Peters WJ. Expression and secretion of IL-2 receptor in trauma patients. Ann Surg 1990; 212:202–208. Curley PJ, McMahon MJ, Lancaster F, Banks RE, Barclay GR, Shefta J, Boylston AW, Whicher JT. Reduction in circulating levels of CD4-positive lymphocytes in acute pancreatitis: relationship to endotoxin, interleukin 6 and disease severity. Br J Surg 1993;80:1312–1315. Widdison AL, Karanjia ND, Alvarez C, Reber HA. Reticuloendothelial function, and efficacy of levamisole for the treatment of pancreatic infection in acute necrotizing pancreatitis. Am J Surg 1992;163:100–104. Browder IW, Sherwood E, Williams D, Jones E, McNamee R, DiLuzio N. Protective effects of glucan-enhanced macrophage function in experimental pancreatitis. Am J Surg 1987;153:25– 33.
Address requests for reprints to: Howard A. Reber, M.D., Department of Surgery, Sepulveda VA Medical Center, 16111 Plummer Street, Building 2, Sepulveda, California 91343. Fax: (818) 8959421. 䉷 1996 by the American Gastroenterological Association 0016-5085/96/$3.00
WBS-Gastro