Abstract
Tissue injury and inflammation in inflammatorybowel disease (IBD) are associated with enhancedmonocytic lysosomal enzyme release. In this study,peripheral monocytes and lamina propria mononuclearcells (LPMNC) were isolated from IBD patients andnormal controls. Cells were stimulated withlipopolysaccharide after treatment with IL-13, IL-4, andIL-10, and enzyme secretion was assessed by using thecorresponding p-nitrophenyl glycosides as substrates.Molecular forms of cathepsin D were examined to describethe mode of enzyme release. IL-10 and IL-4 stronglydown-regulate enzyme secretion in IBD monocytes. IBD monocytes showed a diminished responsiveness tothe inhibitory effect of IL-13. Impaired monocyteresponse was not found with combinations of IL-13 andIL-10 or IL-4 and IL-10. LPMNC from involved IBD mucosa showed significantly higher enzyme secretioncompared with LPMNC from noninvolved IBD mucosa butresponded inefficiently to either IL-4, IL-13, or IL-10alone. However, combined treatment with IL-10 and IL-4 or IL-10 and IL-13 strongly suppressedenzyme release by these cells. Both the precursor andmature forms of cathepsin D were elevated in IBDpatients. While IL-13 reduced mainly the precursor form, the effect of IL-4 and IL-10 concerns both theprecursor and mature form of cathepsin D. Our resultsfavor the potent clinical utility of combined treatment,thus improving chances of developing effective treatments for human IBD.
Similar content being viewed by others
REFERENCES
Mahida YR, Wu K, Jewell DP: Enhanced production of interleukin 1-β by mononuclear cells isolated from mucosa with active ulcerative colitis or Crohn' s disease. Gut 30:835 - 838,1989
Hermanowics A, Gibson PR, Jewell DP: The role of phagocytes in inflammatory bowel disease. Clin Sci 69:241 - 249, 1985
Miura M, Hiwatashi N: Impaired monocyte macrophage s function in patients with Crohn's disease. J Clin Lab Immunol 24:167 - 170, 1987
Mahida YR, Wu K, Jewell DP: Respiratory burst activity of intestinal macrophages in normal and infl ammatory bowel disease. Gut 30:1362 - 1370, 1989
Rugtveit J, Haraldsen G, Hogasen AK, Bakka A, Brandzaeg P, Scott H: Respiratory burst of intestinal macrophage s in inflammatory bowel disease is mainly cause d by CD14+L1+ monocyte ce lls. Gut 37:367 - 373, 1995
Schreiber S, MacDe rmott RP, Raedler A, Pinnau R, Bertowich M, Nash GS: Increased activation of intestinal lamina propria mononuclear cells in inflammatory bowel disease. Gastroenterology 101:1020 - 1030, 1991
Rugtveit J, Brandtzaeg P, Halstensen TS, Fausa O, Scott H: Incre ased macrophage subset in inflammatory bowel disease: Apparent recruitment from peripheral blood monocytes. Gut 35:669 - 674, 1994
Williams JG, Hughes LE, Hallett MB: Toxic oxygen metabolite production by circulating phagocytic ce lls in inflammatory bowel disease. Gut 31:187 - 193, 1990
Ganguly N, Lloyd B, Price C, Kingham J, Lloyd R, Triger D: Acid hydrolases in monocytes from patients with inflammatory bowel disease, chronic liver disease, and rheumatoid arthritis. Lance t, i, 1073 - 1075, 1978
Mee AS, Jewell DP: Monocyte s in inflammatory bowel disease: Monocyte and se rum lysosomal enzyme activity. Clin Sci 58:295 - 300, 1980
Mee AS, Nuttall L, Potter BJ, Jewell DP: Studies on monocytes in inflammatory bowel disease: Factors influencing monocyte lysosomal enzyme activity. Clin Exp Immunol 39:785 - 791, 1980
Scapa E, Neuman M, Eshchar J: In flammatory bowel disease and serum beta-N-ace tylhexosaminidase. Enzyme 43:146 - 150, 1990
Lügering N, Stoll R, Siekmann A, Faulhabe r J, He ese C, Dietrich O, Kucharzik T, Busch H, Hasilik A, Domschke W: Elevated levels of activities of beta-hexosaminidase and alphamannosidase in human immunodeficiency virus-infected patients. J Infect Dis 171:683 - 686, 1995
Kornfeld S: Traffi cking of lysosomal enzyme s in normal and disease states. J Clin Invest 77:1 - 6, 1986
Hasilik A, Neufe ld EF: Biosynthesis of lysosomal enzymes in fi broblasts. Synthesis as precursors of higher molecular weight. J Biol Chem 255:4937 - 4945, 1980
Imort M, Hasilik A, von Figura K: Molecular forms of β-hexoaminidase and cathepsin D in serum and urine of healthy controls and patients with elevated activity of lysosomal enzyme s. Biochem J 213:733 - 740, 1983
Bogdan C, Nathan C: Modulation and macrophage function by transforming growth factor beta, interleukin-4 and interleukin-10. Ann NY Acad Sci 685:713 - 739, 1993
Schreiber S, Heinig T, Panzer U, Reinking R, Bouchard A, Stahl PD, Raedle r A: Impaired re sponse of activated mononuclear phagocyte s to interleukin 4 in infl ammatory bowel disease. Gastroenterology 108:21 - 33, 1995
De Waal Male fyt R, Abrams J, Bennett B, Figdor CG, de Vries JE: IL-10 inhibits cytokine synthesis by human monocytes: an autoregulatory role of IL-10 produced by human monocyte s, J. Exp Med 174: 1209 - 1220, 1991 synthesis by human monocytes: An autoregulatory role of IL-10 produced by human monocyte s. J Exp Med 174:1209 - 1220, 1991
Schreiber S, Heinig T, Thiele HG, Raedle r A: Immunoregulatory role of interleukin 10 in patients with in¯ ammatory bowel disease. Gastroenterology 108:1434 - 1444, 1995
Kucharzik T, Lüge ring N, We igelt H, Adolf M, Domschke W, Stoll R: Immunoregulatory properties of Interleukin-13 in patients with inflammatory bowel disease. Comparison with interleukin-4 and interleukin-10. Clin Exp Immunol 104:483 - 490, 1996
Minty A, Chalon P, Derocq J, Dumont X, Guillemot JC, Kaghad M, Labit C, Leplatois P, Liauzun P, Miloux B, Minty C, Case llas P, Loison G, Lupker J, Shire D, Fe rrara P, Caput D: Interleukin-13 is a new human lymphokine regulating inflammatory and immune responses. Nature 362:248 - 250, 1993
de Waal, Malefyt R, Figdor CG, Huijbens R, Mohan Peterson S, Bennett B, Culpepper J, Dang W, Zurawsky G, de Vries JE: Effects of IL-13 on phenotype, cytokine production, and cytotoxic function of human monocytes. Comparison with IL-4 and modulation with IFN-g or IL-10. J Immunol 151:6370 - 6381, 1993
D'Andrea A, Ma X, Aste-Ame zaga M, Paganin C, Trinchieri G: Stimulatory and inhibitory effects of interleukin (IL)-4 and IL-13 on the production of cytokines by human peripheral blood mononucle ar ce lls: Priming for IL-12 and tumor necrosis factor-a production. J Exp Med 181:537 - 546, 1995
Best WR, Becktel JM, Singleton JW, Ke rn FR: De velopment of a Crohn's disease activity index: National cooperative Crohn's disease study. Gastroente rology 106:782 - 785, 1976
Rachmilewitz D: Coated mesalazine (5-amino-salicylic acid) versus sulphasalazine in the treatment of active ulcerative colitis: A randomized trial. Br Med J 198:82 - 86, 1989
Re inecker HC, Steffen M, Witthoeft T, Pflueger I, Schre iber S, MacDe rmott RP, Raedler A: Enhanced se cre tion of tumour necrosis factor-alpha, IL-6, and IL-1β by isolated lamina propria mononuclear cells from patients with ulcerative colitis and Crohn's disease. Clin Exp Immunol 94:174 - 181, 1993
Laemmli UK: Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature 227:680 - 685, 1970
Towbin H, Staehelin T, Gordon J: Electrophore tic transfer of proteins from polyacrylamide ge ls to nitrocellulose sheets: procedure and some applications. Proc Natl Acad Sci USA 76:4350 - 4354, 1979
Kucharzik T, Lügering N, Adolf M, Domschke W, Stoll R: Syne rgistic effect of immunoregulatory cytokines on peripheral blood monocyte s from patients with infl ammatory bowel disease Dig Dis Sci 42:805 - 812, 1997
Lügering N, Kucharzik T, Lügering A, Winde G, Domschke W, Stoll R: Importance of combined treatment with IL-10 and IL-4, but not IL-13, for inhibiting monocyte re lease of the Ca2+binding protein MRP8/14. Immunology 91:130 - 134, 1997
Mahida YR, Pate l S, Gionchetti P, Vaux D, Jewell DP: Macrophage subpopulations in lamina propria of normal and inflamed colon and terminal ileum. Gut 30:826 - 834, 1989
Cappe llo M, Keshav S, Prince C, Jewell DP, Gordon S: Detection of mRNAs for macrophage products in inflammatory bowel disease by in situhybridisation. Gut 33:1214 - 1219, 1992
Endo T, Fumitaka O, Sone S: LPS-dependent cyclooxygenase-2 induction in human monocytes is down-regulated by IL-13, but not by IFN-g. J Immunol 156:2240 - 2246, 1996
Hart PH, Ahern MJ, Smith MD, Finlay-Jone s JJ: Regulatory effects of IL-13 on synovial fluid macrophages and blood monocyte s from patients with inflammatory arthritis. Clin Exp Immunol 99:331 - 339, 1995
Zurawski G, De Vries JE: Interleukin-13, an interleukin-4 like cytokine that acts on monocyte s and B ce lls, but not on T-ce lls. Immunol Today 15:19 - 26, 1994
Nakagawara A, Nathan CF, Cohn ZA: Hydrogen peroxide me tabolism in human monocytes during differentiation in vitro. J Clin Invest 68:1243 - 1252, 1981
Baldassano RN, Schreiber S, Johnston RB, Muraki T, MacDermott RP: Monocyte s of patients with Crohn's disease are primed for accentuate d rele ase of toxic oxyge n metabolite s: Possible role for endotoxin. Gastroente rology 105:60 - 66, 1993
Rights and permissions
About this article
Cite this article
Lugering, N., Kucharzik, T., Stein, H. et al. IL-10 Synergizes with IL-4 and IL-13 in Inhibiting Lysosomal Enzyme Secretion by Human Monocytes and Lamina Propria Mononuclear Cells from Patients with Inflammatory Bowel Disease. Dig Dis Sci 43, 706–714 (1998). https://doi.org/10.1023/A:1018845526434
Issue Date:
DOI: https://doi.org/10.1023/A:1018845526434