• We are sorry, but NCBI web applications do not support your browser and may not function properly. More information
Logo of gutGutCurrent TOCInstructions to authors
Gut. Apr 1998; 42(4): 470–476.
PMCID: PMC1727082

Increased secretion of pro-inflammatory cytokines by circulating polymorphonuclear neutrophils and regulation by interleukin 10 during intestinal inflammation


Background—Concentrations of pro-inflammatory cytokines are increased in the intestinal mucosa of patients with active inflammatory bowel disease (IBD). Polymorphonuclear neutrophil granulocytes (PMN) are the most abundant cell type in intestinal lesions in IBD. Interleukin 10 (IL-10) is an important contra-inflammatory cytokine which induces downregulation of pro-inflammatory cytokines.
Aims—To investigate whether PMN from patients with IBD or infectious colitis, respectively, secrete increased amounts of pro-inflammatory cytokines and can be regulated by IL-10.
Methods—Secretion (ELISA) as well as corresponding mRNA levels (semiquantitative RT-PCR) of pro-inflammatory cytokines (IL-1β, TNF-α) and of IL-1 receptor antagonist were assessed in peripheral PMN.
Results—PMN from patients with IBD are primed to secrete enhanced amounts of pro-inflammatory cytokines accompanied by detection of corresponding mRNAs in comparison with normal controls. This finding is not specific for IBD but rather reflects intestinal inflammation in general. IL-10 markedly inhibited pro-inflammatory cytokine secretion as well as corresponding mRNA concentrations.
Conclusions—PMN are an important source of pro-inflammatory cytokines in patients with intestinal inflammation and can be downregulated by IL-10.

Keywords: granulocytes; interleukin 1β; interleukin 10; inflammatory bowel disease; intestinal immunity; inflammation; neutrophils; tumour necrosis factor α

Full Text

The Full Text of this article is available as a PDF (161K).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Saverymuttu SH, Peters AM, Lavender JP, Chadwick VS, Hodgson HJ. In vivo assessment of granulocyte migration to diseased bowel in Crohn's disease. Gut. 1985 Apr;26(4):378–383. [PMC free article] [PubMed]
  • Saverymuttu SH, Chadwick VS, Hodgson HJ. Granulocyte migration in ulcerative colitis. Eur J Clin Invest. 1985 Apr;15(2):60–63. [PubMed]
  • Saverymuttu SH, Peters AM, Lavender JP, Pepys MB, Hodgson HJ, Chadwick VS. Quantitative fecal indium 111-labeled leukocyte excretion in the assessment of disease in Crohn's disease. Gastroenterology. 1983 Dec;85(6):1333–1339. [PubMed]
  • Schölmerich J, Schmidt E, Schümichen C, Billmann P, Schmidt H, Gerok W. Scintigraphic assessment of bowel involvement and disease activity in Crohn's disease using technetium 99m-hexamethyl propylene amine oxine as leukocyte label. Gastroenterology. 1988 Nov;95(5):1287–1293. [PubMed]
  • Malizia G, Calabrese A, Cottone M, Raimondo M, Trejdosiewicz LK, Smart CJ, Oliva L, Pagliaro L. Expression of leukocyte adhesion molecules by mucosal mononuclear phagocytes in inflammatory bowel disease. Gastroenterology. 1991 Jan;100(1):150–159. [PubMed]
  • Koizumi M, King N, Lobb R, Benjamin C, Podolsky DK. Expression of vascular adhesion molecules in inflammatory bowel disease. Gastroenterology. 1992 Sep;103(3):840–847. [PubMed]
  • Albelda SM, Smith CW, Ward PA. Adhesion molecules and inflammatory injury. FASEB J. 1994 May;8(8):504–512. [PubMed]
  • Guthrie LA, McPhail LC, Henson PM, Johnston RB., Jr Priming of neutrophils for enhanced release of oxygen metabolites by bacterial lipopolysaccharide. Evidence for increased activity of the superoxide-producing enzyme. J Exp Med. 1984 Dec 1;160(6):1656–1671. [PMC free article] [PubMed]
  • Schreiber S, Raedler A, Stenson WF, MacDermott RP. The role of the mucosal immune system in inflammatory bowel disease. Gastroenterol Clin North Am. 1992 Jun;21(2):451–502. [PubMed]
  • Mahida YR, Wu K, Jewell DP. Enhanced production of interleukin 1-beta by mononuclear cells isolated from mucosa with active ulcerative colitis of Crohn's disease. Gut. 1989 Jun;30(6):835–838. [PMC free article] [PubMed]
  • Ligumsky M, Simon PL, Karmeli F, Rachmilewitz D. Role of interleukin 1 in inflammatory bowel disease--enhanced production during active disease. Gut. 1990 Jun;31(6):686–689. [PMC free article] [PubMed]
  • MacDonald TT, Hutchings P, Choy MY, Murch S, Cooke A. Tumour necrosis factor-alpha and interferon-gamma production measured at the single cell level in normal and inflamed human intestine. Clin Exp Immunol. 1990 Aug;81(2):301–305. [PMC free article] [PubMed]
  • Brynskov J, Tvede N, Andersen CB, Vilien M. Increased concentrations of interleukin 1 beta, interleukin-2, and soluble interleukin-2 receptors in endoscopical mucosal biopsy specimens with active inflammatory bowel disease. Gut. 1992 Jan;33(1):55–58. [PMC free article] [PubMed]
  • Pullman WE, Elsbury S, Kobayashi M, Hapel AJ, Doe WF. Enhanced mucosal cytokine production in inflammatory bowel disease. Gastroenterology. 1992 Feb;102(2):529–537. [PubMed]
  • Schreiber S, Raedler A, Conn AR, Rombeau JL, MacDermott RP. Increased in vitro release of soluble interleukin 2 receptor by colonic lamina propria mononuclear cells in inflammatory bowel disease. Gut. 1992 Feb;33(2):236–241. [PMC free article] [PubMed]
  • Stevens C, Walz G, Singaram C, Lipman ML, Zanker B, Muggia A, Antonioli D, Peppercorn MA, Strom TB. Tumor necrosis factor-alpha, interleukin-1 beta, and interleukin-6 expression in inflammatory bowel disease. Dig Dis Sci. 1992 Jun;37(6):818–826. [PubMed]
  • Isaacs KL, Sartor RB, Haskill S. Cytokine messenger RNA profiles in inflammatory bowel disease mucosa detected by polymerase chain reaction amplification. Gastroenterology. 1992 Nov;103(5):1587–1595. [PubMed]
  • Reinecker HC, Steffen M, Witthoeft T, Pflueger I, Schreiber S, MacDermott RP, Raedler A. Enhanced secretion of tumour necrosis factor-alpha, IL-6, and IL-1 beta by isolated lamina propria mononuclear cells from patients with ulcerative colitis and Crohn's disease. Clin Exp Immunol. 1993 Oct;94(1):174–181. [PMC free article] [PubMed]
  • Dinarello CA, Wolff SM. The role of interleukin-1 in disease. N Engl J Med. 1993 Jan 14;328(2):106–113. [PubMed]
  • Nicholls S, Stephens S, Braegger CP, Walker-Smith JA, MacDonald TT. Cytokines in stools of children with inflammatory bowel disease or infective diarrhoea. J Clin Pathol. 1993 Aug;46(8):757–760. [PMC free article] [PubMed]
  • Grisham MB, Granger DN. Neutrophil-mediated mucosal injury. Role of reactive oxygen metabolites. Dig Dis Sci. 1988 Mar;33(3 Suppl):6S–15S. [PubMed]
  • Faden H, Rossi TM. Chemiluminescent response of neutrophils from patients with inflammatory bowel disease. Dig Dis Sci. 1985 Feb;30(2):139–142. [PubMed]
  • Anton PA, Targan SR, Shanahan F. Increased neutrophil receptors for and response to the proinflammatory bacterial peptide formyl-methionyl-leucyl-phenylalanine in Crohn's disease. Gastroenterology. 1989 Jul;97(1):20–28. [PubMed]
  • Kelleher D, Feighery C, Weir DG. Chemiluminescence by polymorphonuclear leucocyte subpopulations in chronic inflammatory bowel disease. Influence of the cell separation procedure. Digestion. 1990;45(3):158–165. [PubMed]
  • Baldassano RN, Schreiber S, Johnston RB, Jr, Fu RD, Muraki T, MacDermott RP. Crohn's disease monocytes are primed for accentuated release of toxic oxygen metabolites. Gastroenterology. 1993 Jul;105(1):60–66. [PubMed]
  • Griga T, Tromm A, Schwegler U, May B. Enhanced superoxide anion release of normal neutrophil granulocytes primed with sera of patients with inactive inflammatory bowel disease. Z Gastroenterol. 1995 Jul;33(6):345–348. [PubMed]
  • Andus T, Gross V, Caesar I, Krumm D, Hosp J, Gerok W, Schölmerich J. PMN-elastase in assessment of patients with inflammatory bowel disease. Dig Dis Sci. 1993 Sep;38(9):1638–1644. [PubMed]
  • Adeyemi EO, Hodgson HJ. Faecal elastase reflects disease activity in active ulcerative colitis. Scand J Gastroenterol. 1992;27(2):139–142. [PubMed]
  • Bazzoni F, Cassatella MA, Laudanna C, Rossi F. Phagocytosis of opsonized yeast induces tumor necrosis factor-alpha mRNA accumulation and protein release by human polymorphonuclear leukocytes. J Leukoc Biol. 1991 Sep;50(3):223–228. [PubMed]
  • Cassatella MA, Meda L, Bonora S, Ceska M, Constantin G. Interleukin 10 (IL-10) inhibits the release of proinflammatory cytokines from human polymorphonuclear leukocytes. Evidence for an autocrine role of tumor necrosis factor and IL-1 beta in mediating the production of IL-8 triggered by lipopolysaccharide. J Exp Med. 1993 Dec 1;178(6):2207–2211. [PMC free article] [PubMed]
  • Cassatella MA. The production of cytokines by polymorphonuclear neutrophils. Immunol Today. 1995 Jan;16(1):21–26. [PubMed]
  • Vieira P, de Waal-Malefyt R, Dang MN, Johnson KE, Kastelein R, Fiorentino DF, deVries JE, Roncarolo MG, Mosmann TR, Moore KW. Isolation and expression of human cytokine synthesis inhibitory factor cDNA clones: homology to Epstein-Barr virus open reading frame BCRFI. Proc Natl Acad Sci U S A. 1991 Feb 15;88(4):1172–1176. [PMC free article] [PubMed]
  • de Waal Malefyt R, Yssel H, Roncarolo MG, Spits H, de Vries JE. Interleukin-10. Curr Opin Immunol. 1992 Jun;4(3):314–320. [PubMed]
  • Fiorentino DF, Zlotnik A, Mosmann TR, Howard M, O'Garra A. IL-10 inhibits cytokine production by activated macrophages. J Immunol. 1991 Dec 1;147(11):3815–3822. [PubMed]
  • Ralph P, Nakoinz I, Sampson-Johannes A, Fong S, Lowe D, Min HY, Lin L. IL-10, T lymphocyte inhibitor of human blood cell production of IL-1 and tumor necrosis factor. J Immunol. 1992 Feb 1;148(3):808–814. [PubMed]
  • de Waal Malefyt R, Abrams J, Bennett B, Figdor CG, de Vries JE. Interleukin 10(IL-10) inhibits cytokine synthesis by human monocytes: an autoregulatory role of IL-10 produced by monocytes. J Exp Med. 1991 Nov 1;174(5):1209–1220. [PMC free article] [PubMed]
  • Schreiber S, Heinig T, Thiele HG, Raedler A. Immunoregulatory role of interleukin 10 in patients with inflammatory bowel disease. Gastroenterology. 1995 May;108(5):1434–1444. [PubMed]
  • Cassatella MA, Meda L, Gasperini S, Calzetti F, Bonora S. Interleukin 10 (IL-10) upregulates IL-1 receptor antagonist production from lipopolysaccharide-stimulated human polymorphonuclear leukocytes by delaying mRNA degradation. J Exp Med. 1994 May 1;179(5):1695–1699. [PMC free article] [PubMed]
  • van Deventer SJ, Elson CO, Fedorak RN. Multiple doses of intravenous interleukin 10 in steroid-refractory Crohn's disease. Crohn's Disease Study Group. Gastroenterology. 1997 Aug;113(2):383–389. [PubMed]
  • Best WR, Becktel JM, Singleton JW, Kern F., Jr Development of a Crohn's disease activity index. National Cooperative Crohn's Disease Study. Gastroenterology. 1976 Mar;70(3):439–444. [PubMed]
  • Rachmilewitz D. Coated mesalazine (5-aminosalicylic acid) versus sulphasalazine in the treatment of active ulcerative colitis: a randomised trial. BMJ. 1989 Jan 14;298(6666):82–86. [PMC free article] [PubMed]
  • Gasperini S, Donini M, Dusi S, Cassatella MA. Interleukin-10 decreases tyrosine phosphorylation of discrete lipopolysaccharide-induced phosphoproteins in human granulocytes. Biochem Biophys Res Commun. 1995 Apr 6;209(1):87–94. [PubMed]
  • Yam LT, Li CY, Crosby WH. Cytochemical identification of monocytes and granulocytes. Am J Clin Pathol. 1971 Mar;55(3):283–290. [PubMed]
  • Bienvenu J, Coulon L, Doche C, Gutowski MC, Grau GE. Analytical performances of commercial ELISA-kits for IL-2, IL-6 and TNF-alpha. A WHO study. Eur Cytokine Netw. 1993 Nov-Dec;4(6):447–451. [PubMed]
  • Chomczynski P, Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem. 1987 Apr;162(1):156–159. [PubMed]
  • Wang AM, Doyle MV, Mark DF. Quantitation of mRNA by the polymerase chain reaction. Proc Natl Acad Sci U S A. 1989 Dec;86(24):9717–9721. [PMC free article] [PubMed]
  • Raab Y, Gerdin B, Ahlstedt S, Hällgren R. Neutrophil mucosal involvement is accompanied by enhanced local production of interleukin-8 in ulcerative colitis. Gut. 1993 Sep;34(9):1203–1206. [PMC free article] [PubMed]
  • Monajemi H, Meenan J, Lamping R, Obradov DO, Radema SA, Trown PW, Tytgat GN, Van Deventer SJ. Inflammatory bowel disease is associated with increased mucosal levels of bactericidal/permeability-increasing protein. Gastroenterology. 1996 Mar;110(3):733–739. [PubMed]
  • Dinarello CA. Interleukin-1 and interleukin-1 antagonism. Blood. 1991 Apr 15;77(8):1627–1652. [PubMed]
  • Lenardo MJ, Baltimore D. NF-kappa B: a pleiotropic mediator of inducible and tissue-specific gene control. Cell. 1989 Jul 28;58(2):227–229. [PubMed]
  • Baldwin AS., Jr The NF-kappa B and I kappa B proteins: new discoveries and insights. Annu Rev Immunol. 1996;14:649–683. [PubMed]
  • Colotta F, Re F, Polentarutti N, Sozzani S, Mantovani A. Modulation of granulocyte survival and programmed cell death by cytokines and bacterial products. Blood. 1992 Oct 15;80(8):2012–2020. [PubMed]

Figures and Tables

Figure 1
Lipopolysaccharide induced secretion of IL-1β by peripheral blood PMN.
Figure 2
Lipopolysaccharide induced secretion of TNF-α by peripheral blood PMN.
Figure 3
Lipopolysaccharide induced secretion of IL-1ra by peripheral blood PMN.
Figure 4
Longitudinal follow up of patients with mucosal inflammation.
Figure 5
Downregulation of PMN pro-inflammatory cytokine secretion by IL-10.
Figure 6
Pro-inflammatory cytokine mRNA in PMN and regulation by IL-10.

Articles from Gut are provided here courtesy of BMJ Group


Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...


  • MedGen
    Related information in MedGen
  • PubMed
    PubMed citations for these articles
  • Substance
    PubChem Substance links