The role of interleukin-10 in critical illness

Current Opinion in Infectious Diseases

Volumn 13, Issue 3, 2000, Pages 221-226

  Opal, Steven M ^a,b   Huber, Christian E ^a  

^a BROWN UNIVERSITY   (United States)

^b MEMORIAL HOSPITAL OF RHODE ISLAND   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

CD4 ANTIGEN; CHEMOKINE; CYTOKINE; DNA; GAMMA INTERFERON; GRANULOCYTE COLONY STIMULATING FACTOR; GRANULOCYTE MACROPHAGE COLONY STIMULATING FACTOR; IMMUNOGLOBULIN; IMMUNOGLOBULIN ENHANCER BINDING PROTEIN; IMMUNOGLOBULIN G; INTERLEUKIN 10; INTERLEUKIN 12; INTERLEUKIN 6; INTERLEUKIN 8; MACROPHAGE INFLAMMATORY PROTEIN 1ALPHA; MESSENGER RNA; MITOGEN ACTIVATED PROTEIN KINASE; NITRIC OXIDE; OXYGEN RADICAL; PROSTAGLANDIN; PROTEIN TYROSINE KINASE; TUMOR NECROSIS FACTOR; TUMOR NECROSIS FACTOR RECEPTOR; TYROSINE;

CRITICAL ILLNESS; DRUG MECHANISM; HUMAN; IMMUNE RESPONSE; INFECTION; INFLAMMATION; MOLECULAR BIOLOGY; PSEUDOMONAS AERUGINOSA; REVIEW; STRUCTURE ACTIVITY RELATION;

EID: 0034077003     PISSN: 09517375     EISSN: None     Source Type: Journal    
DOI: 10.1097/00001432-200006000-00004     Document Type: Review

References (36)

1. 1 Opal SM, Wherry JC, Grint P. Interleukin-10: Potential benefits and possible risks in clinical infectious diseases. Clin Infect Dis 1998; 27:1497-1507. This is a comprehensive review of the literature that examines the role of IL-10 in localized and systemic infectious processes. IL-10 has a myriad of inflammatory properties affecting multiple effector cells of the innate and acquired immune response.
2. 2 Zdanob A, Schalk-Hihi C, Wlodawer A. Crystal structure of human interleukin-10 at 1.6 Å resolution in a model of a complex with its soluble receptor. Protein Science 1996; 5:1956-1962.
3. 3 Berman HM, Westbrook J, Feng Z, Gilliland G, Bhat TN, Weissig M et al. The protein data bank. Nucleic Acid Res 2000; 28:235-242.
4. 4 Van der Poll T, van Deventer SJ. Cytokines and anticytokines in the pathogenesis of sepsis. Infect Dis Clin North Am 1999; 13:413-426. The complex interactions between pro-inflammatory cytokine networks and anti-inflammatory cytokines are reviewed in this paper. The central role of interleukin-10 in regulation of innate immune response in human sepsis is emphasized.
5. 5 Lindmark E, Tenno T, Chen J, Siegbahn A. IL-10 inhibits LPS-induced human monocyte tissue factor expression in whole blood. Br J Haematol 1998; 102:597-604. A number of pro-inflammatory cytokines upregulate tissue factor expression in patients with severe sepsis. This induces activation of the extrinsic clotting system and contributes to coagulation activation in sepsis. These authors demonstrate that IL-10, but not IL-4 or IL-13, attenuates tissue factor expression in a whole blood lipopolysaccharide stimulation assay.
6. 6 Selzman CH, Shames BD, Miller SA, Pulido EJ, Meng X, McIntyre RC, Harken AH. Therapeutic implications of interleukin-10 in surgical disease. Shock 1998; 10:309-318. This is a review of the role of IL-10 as a marker and potential therapeutic agent in inflammatory and immune-mediated diseases. The anti-inflammatory activity of IL-10 may be exploited clinically as a therapeutic option in a variety of surgical disease entities.
7. 7 Coicischowsky C, Schöning B, Lanksch WR, Volk H-D, Döcke W-D. Catecholamine-induced interleukin-10 release: a key mechanism in systemic immunodepression after brain injury. Crit Care 1999; 3:107-111. The mechanism(s) responsible for systemic immunosuppression following severe head injury is poorly understood. This review paper describes the evidence that indicates neuroimmune activation via the sympathetic nervous system is responsible for the anti-inflammatory response following head injury. Catecholamine-induced systemic IL-10 release results in neutrophil and monocyte deactivetion and contributes to the immunoauppreasive effects of severe head injury.
8. 8 Moldawer LL, Edwards PD, Josephs M, Minter RN, Copeland III EM, MacKay SLD. Application of gene therapy to acute inflammatory diseases. Shock 1999; 12:83-101. These investigators describe the promise and the problems associated with gene therapy in the treatment of acute inflammatory diseases. This review covers the potential use of IL-10 transgenes in sepsis, pancreatitis, inflammatory bowel disease and inflammatory arthritis. The relative merits of gene therapy over other treatment strategies, tissue specific expression systems, viral and non-viral delivery systems, and the future of gene technology are described in detail.
9. 9 Krieg AM. An innate immune defense mechanism based on the recognition of CpG motifs in microbial DNA. J Lab Clin Med 1996; 128:128-133.
10. 10 David SA, Silverstein R, Amura CR, Kielian T, Morrison DC. Lipopolyamines: novel anti-endotoxin compounds that reduce mortality in experimental sepsis caused by Gram-negative bacteria. Antimicrob Agents Chemother 1999; 43:912-919. Lipopolyamines used for DNA transfection models (lipofection) was found to have an unexpected advantageous property. It was found that certain lipopolyamines avidly bind to lipopolysaccharide and prevent pro-inflammatory cytokine induction in lipopolysaccharide challenge systems. Lipopolyamines were shown to prevent lethality in endotoxin-challenged mice.
11. 11 Ebong S, Call D, Nemzek J, Bolgos G, Newcomb D, Remick D. Immunopathologic alterations in murine models of sepsis of increasing severity. Infect Immun 1999; 67:6603-6610. Using a cecal ligation and puncture model, these investigators demonstrated that there is a stepwise increase in both pro-and anti-inflammatory cytokine production in animals with intra-abdominal sepsis of increasing severity. IL-10 levels were much higher in the peritoneal fluid when compared to the systemic circulation, This was true for pro-inflammatory cytokines and other anti-inflammatory cytokines as well. Local cytokine responses are a more sensitive indicator of disease severity than systemic biologic response mediators in the presence of septic states following localized infectious processes.
12. 12 Song GY, Chung C-S, Chaudry IH, Ayala A. What is the role of interleukin-10 in polymicrobial sepsis: anti-inflammatory agent or immunosuppressant? Surgery 1999; 126:378-383. In a series of experiments with wild-type and IL-10 knock-out mice, these investigators study the potential benefits and potential deleterious effects of IL-10 and IL-10 deficiency in polymicrobial sepsis. An interesting finding was obtained. Anti-IL-10 monoclonal antibody not protective if given at the time of the CLP; however, if anti-IL-10 antibody was given 12 hours after the surgery, the animals survived. Results are compatible with the hypothesis that IL-10 may be important in attenuating the initial systemic inflammatory response, yet the cytokine impairs the late host response to the infectious process in unchecked intra-abdominal sepsis.
13. 13 Lyons A, Goebel A, Mannick JA, Lederer JA. Protective effects of early interteukin 10 antagonism on injury-induced immune dysfunction. Arch Surg 1999; 134:1317-1323. In a combination of a murine burn and polymicrobial sepsis models, the authors showed that early administration of anti-IL-10 antibodies improves survival and restores the injury-induced immune suppression in polymicrobial sepsis following burn injury. Cytokine measurements attribute this improvement to the promotion of inflammatory Th1-like immunity, which normally would be suppressed by elevated IL-10 levels after burn injury. IL-10 administration 3 days after burn injury had no beneficial effect.
14. 14 Song GY, Chung CS, Schwacha MG, Jarrar D, Chaudry IH, Ayala A. Splenic immune suppression in sepsis: a role for IL-10-induced changes in P38 MAPK signaling. J Surg Res 1999; 83:36-43. The transcriptional activator p39 MAPK might be a favorable candidate for IL-10 signal transduction pathways. In a murine intra-abdominal sepsis model (cecal ligation and puncture), the p38 MAPK was increased and Th1 cytokines (IL-2, IFN-γ) production in splenocytes was depressed after mitogenic stimulation. Blocking IL-10 by antibodies or using IL-10 knockout mice restored the Th1 function to normal and decreased p36 MAPK levels.
15. 15 Kavanagh EK, Kell MR, Goebel A, Soberg CC, Mannick JA, Lederer JA. Interleukin-10 is not essential for survival or for modulating T-cell function after injury. Surgery 1999; 126:456-462. After burn injury, IL-10 knockout mice had the same survival as wild-type mice. The investigators did not show the same importance of IL-10 in burn injury that has been demonstrated in sepsis and severe injury studies.
16. 16 Kurahashi K, Kajikawa O, Sawa T, O'Hara M, Gropper MA, Frank DW, et al. Pathogenesis of septic shock in Pseudomonas aeruginosa pneumonia. J Clin Invest 1999; 101:734-760. In a lapine model of septic shook from installation of Pseudomonas aeruginosa in lung tissue, rabbits could be prevented by the administration of human interleukin-10, Septic shock was only observed by cytotoxin-inducing strains of Pseuodomonas aeruginosa in lung tissue. Interestingly, intravenous administration of the same organism generated systemic TNF levels but failed to produce shock in this rabbit model.
17. 17 Remick DG, Garg SJ. Newcomb DE, Wollenbarg G, Huie TK, Bolgos GL. Exogenous IL-10 fails to decrease mortality or morbidity of sepsis. Crit Care Med 1998; 26:895-904. In a cecal ligation and puncture model in mice, IL-10 failed to reduce inflammatory cytokine production, neutrophil infiltration into the lung or peritoneum, or affect the outcome in this experimental model of intra-abdominal sepsis. Exogenous administration of IL-10 may benefit the septic host with complex polymicrobial sepsis.
18. 18 Van Dissel JT, van Langevelde P, Westendorp RGJ, Kwappenberg K, Frölich M. Anti-inflammatory cytokine profile and mortality in febrile patients. Lancet 1998; 351:950-953. These investigators identified elevated plasma IL-10 levels in community-acquired febrile illness as a predictive marker for high mortality. Cytokine levels in 464 patients were measured and correlated with clinical outcome. High IL-10 levels on admission predicted a twofold higher mortality; in general non-survivors had higher IL-10/TNF alpha ratios. These data caution against the use of pro-inflammatory cytokine inhibition therapy in the management of sepsis.
19. 19 Gogos CA, Drosou E, Bassaris HP, Skoutelis A. Pro versus anti-inflammatory cytokine profile in patients with severe sepsis: a marker for prognosis and future therapeutic options. J Infect Dis 2000; 181:176-180. These investigators followed sixty-five severely septic patients with serial measurements of pro-and anti-inflammatory cytokines in the systemic circulation. While both pro-and anti-inflammatory cytokines were elevated in severe sepsis, the ratio between IL-10 and TNF was consistently higher in patients who were non-survivors when compared to survivors. Excess production of the anti-inflammatory cytokine IL-10 was associated with increased disease severity and a fatal outcome.
20. 20 Glynn P, Coakley R, Kilgallen I, Murphy N, O'Neill S. Circulating interleukin 6 and interleukin 10 in community acquired pneumonia. Thorax 1999; 54:51-55. For the first time IL-10 has been demonstrated to play a role in community-acquired pneumonia. This was demonstrated by measuring IL-6 and IL-10 levels in 38 patients divided into two groups: those patients fulfilling systemic inflammatory response syndrome (SIRS) criteria and those that did not. Cytokine levels correlated with clinical scores, and high-level IL-10 was especially present in SIRS patients and in patients with circulating IL-6 levels. The clinical utility and prognostic significance of cytokine measurement in community-acquired pneumonia deserve further study.
21. 21 Edelson MB, Bagwell CE, Rozycki HJ. Circulating pro-and counterinflammatory cytokine levels and severity in necrotizing enterocolitis. Pediatrics 1999; 103:766-771. In this prospective study, serial serum cytokine levels in short intervals were determined in newborn infants between onset and after 3 days of necrotizing enterocolitis. Eight hours after onset, elevated IL-10 predicted progression to severe necrotizing enterocolitis with a sensitivity of 100% and might therefore serve as a clinical marker. In the course of disease, immunosuppressive cytokines like IL-10 were released after a delay of several hours.
22. 22 Flach R, Majetschak M, Heukamp T, Jennissen V, Flohé S, Börgermann J, et al. Relation of ex vivo stimulated blood cytokine synthesis to post-traumatic sepsis. Cytokine 1999; 11:173-178. In this study in posttraumatic patients, cytokine synthesis in blood was measured after ex-vivo endotoxin stimulation. IL-10 did not exhibit prognostic value, whereas TNF alpha, IL-6, and IL-8 differed significantly in those patients who later developed sepsis compared to the non-sepsis group.
23. 23 Taniguchi T, Koido Y, Aiboshi J, Yamashita T, Suzaki S, Kurokawa A. Change in the ratio of interleukin-6 to interleukin-10 predicts a poor outcome in patients with systemic inflammatory response syndrome. Crit Care Med 1999; 27:1262-1264. Decreased IL-10 levels or an increase in plasma IL-6/IL-10 ratio in 25 patients fulfilling SIRS criteria were predictive of non-survival. Although only six patients were non-survivors in this prospective study, these parameters are worthy candidates for future study as prognostic markers in sepsis. It should be noted that these results are in conflict with other clinical reports. [17••, 18••].
24. 24 Arnalich F, Lopez J, Codoceo R, Jiminez M, Madero R, Montiel C. Relationship of plasma leptin to plasma cytokines and human survival in sepsis and septic shock. J Infect Dis 1999; 180:908-911. IL10 was elevated in 28 patients early in the course of severe sepsis compared to healthy controls, and more elevated in 14 patients with septic shock. Overall, IL-10 was significantly elevated in survivors. These data demonstrate the need for more study of IL-10 kinetics in the sepsis syndrome.
25. 25 Oberhoffer M, Vogelsang H, Russwurm S, Hartung T, Reinhart K. Outcome prediction by traditional and new markers of inflammation in patients with sepsis. Clin Chem Lab Med 1999; 37:363-368. In this investigation, IL-10 is a poor prognostic parameter for mortality from sepsis. In 242 septic patients, the best predictive marker for non-survival was procalcitonin, followed by TNF, IL-6 and C-reactive protein. The worst prognostic parameters were body temperature, followed by total leukocyte counts and IL-10 levels.
26. 26 Donnelly SC, Strieter RM, Reid PT, Kunkel SL, Burdick MD, Armstrong I, et al. The association between mortality rates and decreased concentrations of interleukin-10 and interleukin-1 receptor antagonist in the lung fluids of patients with the adult respiratory distress syndrome. Ann Intern Med 1996; 125:191-196.
27. 27 Lemaire LCJM, van Lanschot JJB, van der Poll T, Buurman WA, van Deventer SJH, Gouma DJ. Lymph of patients with a systemic inflammatory response syndrome inhibits lipopolysaccharide-induced cytokine production. J Infect Dis 1998; 178:883-886. Sampling of thoracic duct lymph in septic patients and normal control patients inhibited lipopolysaccharide-induced pro-inflammatory cytokine production in an ex-vivo assay. IL-10 levels were found to be present in high concentrations in lymph in both septic patients and patients without systemic inflammatory response syndrome. Interstitial fluids may contain substantial quantities of IL-10, which serve to produce a state of relative lipopolysaccharide tolerance in extravascular fluids.
28. 28 Schröder J, Kahlke V, Staubach KH, Zabel P, Stüber F. Gender differences in human sepsis. Arch Surg 1998; 133:1200-1205. The results of a prospective study involving 58 patients suggest that a different therapeutic approach may be needed in the care of female and male septic patients. Septic men had a significant higher mortality when matched to women with similar characteristics regarding age, cause and underlying disease severity. The authors demonstrated higher levels of IL-10 in women than in men. This may contribute to a differential cytokine responsiveness and a different approach to septic patients based upon gender.
29. 29 Flohé S, Börgermann J, Dominguez FE, Majetschak M, Lim L, Kreuzfelder E. Influence of granulocyte-macrophage colony-stimulating factor (GM-CSF) on whole blood endotoxin responsiveness following trauma or cardiopulmonary bypass and severe sepsis. Shock 1999; 21:17-24. These investigators studied the influence of GM-CSF impaired immune response in patients with surgical disease and sepsis. Evidence of immunosuppression was found as evidenced by reduced endotoxin-induced HLA-DR expression on monocytes and TNF alpha production. Ex-vivo stimulation with GM-CSF was able to override the immunodepression induced by IL-10, TGF-beta, and PGE2.
30. 30 Fanning NF, Kell MR, Shorten GD, Kirwan WO, Bouchier-Hayes D, Cotter TG, Redmond HP. Circulating granulocyte macrophage colony-stimulating factor in plasma of patients with the systemic inflammatory response syndrome delays apoptosis through inhibition of spontaneous reactive oxygen species generation. Shock 1999; 11:167-174. IL-10 appears to modulate neutrophil apoptosis and their reactive oxygen species production. Neutrophils isolated from patients with SIRS have delayed neutrophil apoptosis as monitored using annexin V-FITC and terminal deoxyuridine triphosphate (dUTD) nick end labeling (TUNEL) flow cytometry methods. This suppression was reversed by addition of neutralizing GM-CSF antibodies or recombinant human IL-10 to SIRS plasma. Regulation of neutrophil apoptosis may prevent cellular injury for oxidant stress during periods of tissue infiltration by activated neutrophils.
31. 31 Zedler S, Bone RC, Baue AE, von Donnersmarck GH, Faist E. T-cell reactivity and its predictive role in immunosuppression after burns. Crit Care Med 1999; 27:66-72. These investigators demonstrated that CD8+ T cells (rather than CD4 T cells) are the principal source of IL-4-induced phenotypic shift to a Th2-type cytokine response in burn patients. Patients who developed a dominant anti-inflammatory cytokine response following severe injury were more likely to succumb from severe sepsis.
32. 32 Schinkel C, Sendter R, Zimmer S, Faist E. Functional analysis of monocyte subsets in surgical sepsis. J Trauma 1998; 44:743-748. Septic patients develop alterations in their circulating monocytic cell populations that may have important functional consequences. Fc receptor density increases on cell surfaces of monocytes in septic patients but HLA-DR expression decreases. These are both IL-10-mediated monocyte effects that limit antigen presentation for T cell populations. This suggests that IL-10 may play a significant role in the suppression of cell mediated immune function frequently observed in severe sepsis.
33. 33 Klava A, Windsor ACJ, Farmery SM, Woodhouse LF, Reynolds JV, Ramadan CW, et al. Interleukin-10: a role in the development of post operative immunosuppression. Arch Sung 1997; 132:425-429.
34. 34 Haupt W, Zirngibl H, Stehr A, Riese J, Holzheimer RG, Hohenberger W. Tumor necrosis factor-α and interleukin-10 production in septic patients and the regulatory effect of plasma. Eur J Surg 1999; 165:95-100. Septic plasma markedly inhibited TNF and modestly impaired IL-10 synthesis in whole blood assays of normal plasma samples following ex-vivo lipopolysaccharide stimulation. This study demonstrates that the immunomodulatory effects of humoral factors in septic plasma need to be considered in addition to cellular and genetic elements in control of the human immune response to septic stimuli.
35. 35 Cooper PJ, Fekade D, Remick DG, Grint P, Wherry J, Griffin GE. Recombinant human interleukin-10 fails to alter pro-inflammatory cytokine production or physiologic changes associated with Jarisch-Herxheimer reaction. J Infect Dis 2000; 281:903-909. IL-10 failed to protect patients against the hemodynamic derangements or pro-inflammatory cytokine response following antibiotic-induced Jarisch-Herxheimer reactions in patients with Borrelia recurrentis infection. These results are surprising since anti-TNF antibodies are effective in the same clinical setting. While IL-10 did not interfere with neutrophil-mediated clearance of spirochetes from the circulation, the failure of IL-10 to limit the cytokine response in these patients with louse-borne relapsing fever is disappointing. The explanation for the failure of IL-10 to protect against this reaction remains obscure.
36. 36 Fekade D, Knox K, Hussein K, et al. Prevention of Jarisch-Herxheimer reactions by treatment with antibodies against tumor necrosis factor α. N Engl J Med 1996; 335:331-315.