Interleukin-6 and soluble interleukin-6 receptor in the colonic mucosa of inflammatory bowel disease
Takehiko Hosokawa, Kazuo Kusugami, Kenji Ina, Takafumi Ando, Masataka Shinoda, Akira Imada, Masahiro Ohsuga, Tetsu Sakai, Toshihiro Matsuura, Katsuki Ito,
Kenmei Kaneshiro,
Katsuki Ito
Second Department of Surgery, Nagoya University School of Medicine, Nagoya and
Search for more papers by this authorTakehiko Hosokawa, Kazuo Kusugami, Kenji Ina, Takafumi Ando, Masataka Shinoda, Akira Imada, Masahiro Ohsuga, Tetsu Sakai, Toshihiro Matsuura, Katsuki Ito,
Kenmei Kaneshiro,
Katsuki Ito
Second Department of Surgery, Nagoya University School of Medicine, Nagoya and
Search for more papers by this author
Correspondence:
DrKKusugami
First Department of Internal Medicine, Nagoya University School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan. Email: <
[email protected]>
Abstract
Background : Interleukin-6 (IL-6) has multiple immunological effects on a wide variety of cells and tissues. The expression of IL-6 and IL-6 receptor (IL-6R) may be important to the pathogenesis of inflammatory bowel disease (IBD).
Methods : In the present study, we examined whether mucosal IL-6 and soluble IL-6R were associated with the pathophysiology of IBD using the colonic mucosal specimens obtained from patients with IBD. Enzyme-linked immunosorbent assay was used to measure the levels of IL-6 and sIL-6R in organ cultures of mucosal tissues and in cell cultures of fractionated mucosal cells as well as in the serum. Expression of IL-6 and IL-6R was analysed by reverse transcription–polymerase chain reaction analysis using freshly isolated lamina propria mononuclear cells (LPMC).
Results : The levels of IL-6 and sIL-6R in organ cultures were substantially elevated in patients with IBD, especially in those with histologically active inflammation. In contrast, considerably higher levels of sIL-6R were detected in patients with other types of colonic inflammation who were included as inflammatory controls, but elevation of IL-6 was less prominent in such patients. The positivity for expression of IL-6 and IL-6R mRNA in LPMC was in parallel with the results obtained in organ cultures. In cell cultures, mucosal macrophages were the main cell type producing both IL-6 and sIL-6R on a per cell basis and other cell fractions including colonic epithelial cells and lymphocytes produced substantially lower amounts of these molecules. The levels of IL-6 and sIL-6R in organ cultures, but not those in the serum, showed a significantly positive correlation with the degree of clinical disease activity in patients with IBD.
Conclusions : Enhanced IL-6/sIL-6R-mediated immune and inflammatory responses may be implicated, at least partly, in the continuation of intestinal inflammation in patients with IBD.
© 1999 Blackwell Science Asia Pty Ltd
REFERENCES
- 1 Sartor RB. Cytokines in intestinal inflammation: Pathophysiological and clinical considerations. Gastroenterology 1994; 106: 533 9.
- 2 Kishimoto T. The biology of interleukin-6. Blood 1989; 74: 1 10.
- 3 Garman RD, Jacobs KA, Clark SC et al. B-cell-stimulatory factor 2 (β2 interferon) functions as a second signal for interleukin 2 production by mature murine T cells. Proc. Natl Acad. Sci. USA 1987; 84: 7629 33.
- 4 Vink A, Uyttenhove C, Wauters PV, Snick J. Accessory factors involved in murine T cell activation. Distinct roles of interleukin 6, interleukin 1 and tumor necrosis factor. Eur. J. Immunol. 1990; 20: 1 6.
- 5 Muraguchi A, Hirano T, Tang B et al. The essential role of B cell stimulatory factor 2 (BSF-2/IL-6) for the terminal differentiation of B cells. J. Exp. Med. 1988; 167: 332 44.
- 6 Gauldie J, Richards C, Harnish D, Lansdorp P, Baumann H. Interferon β2/B-cell stimulatory factor type 2 shares identity with monocyte-derived hepatocyte-stimulating factor and regulates the major acute phase protein response in liver cells. Proc. Natl Acad. Sci. USA 1987; 84: 7251 5.
- 7 Mahida YR, Kurlac L, Gallagher A, Hawkey CJ. High circulating concentrations of interleukin-6 in active Crohn’s disease but not ulcerative colitis. Gut 1991; 32: 1531 4.
- 8 Gross V, Andus T, Caesar I, Roth M, Scholmerich J. Evidence for continuous stimulation of interleukin-6 production in Crohn’s disease. Gastroenterology 1992; 102: 514 19.
- 9 Mitsuyama K, Sata M, Tanikawa K. Significance of interleukin-6 in patients with inflammatory bowel disease. Gastroenterol. Jpn 1991; 26: 20 8.
- 10 Schurmann G, Betzler M, Post S et al. Soluble interleukin-2 receptor, interleukin-6 and interleukin-1β in patients with Crohn’s disease and ulcerative colitis: Preoperative levels and postoperative changes of serum concentrations. Digestion 1992; 51: 51 9.
- 11 Hyams JS, Fitzgerald JE, Treem WR, Wyzga N, Kreutzer DL. Relationship of functional and antigenic interleukin 6 to disease activity in inflammatory bowel disease. Gastroenterology 1993; 104: 1285 92.
- 12 Niederau C, Backmerhoff F, Schumacher B, Niederau C. Inflammatory mediators and acute phase proteins in patients with Crohn’s disease and ulcerative colitis. Hepatogastroenterology 1997; 44: 90 107.
- 13 Mahida YR, Gallagher A, Kurlak L et al. Plasma and tissue interleukin-2 receptor levels in inflammatory bowel disease. Clin. Exp. Immunol. 1990; 82: 75 80.
- 14 Castell JV, Geiger T, Gross V et al. Plasma clearance, organ distribution and target cells of interleukin-6/hepatocyte-stimulating factor in the rat. Eur. J. Biochem. 1988; 177: 357 61.
- 15 Mitsuyama K, Sakaki E, Toyonaga A et al. Colonic mucosal interleukin-6 in inflammatory bowel disease. Digestion 1991; 50: 104 11.
- 16 Reinecker HC, Steffen M, Witthoeft T et al. Enhanced secretion 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. 1993; 94: 174 81.
- 17 Kusugami K, Fukatsu A, Tanimoto M et al. Elevation of interleukin-6 in inflammatory bowel disease is macrophage- and epithelial cell-dependent. Dig. Dis. Sci. 1995; 40: 949 59.
- 18 Taga T, Hibi M, Hirata Y et al. Interleukin-6 triggers the association of its receptor with a possible signal transducer, gp130. Cell 1989; 58: 573 81.
- 19 Kishimoto T, Akira S, Narazaki M, Taga T. Interleukin-6 family of cytokines and gp130. Blood 1995; 86: 1243 54.
- 20 Honda M, Yamamoto S, Cheng M et al. Human soluble IL-6 receptor: Its detection and enhanced release by HIV infection. J. Immunol. 1992; 148: 2175 80.
- 21 Gaillard JP, Bataille R, Brailly H et al. Increased and highly stable levels of functional soluble interleukin-6 receptor in sera of patients with monoclonal gammapathy. Eur. J. Immunol. 1993; 23: 820 4.
- 22 Yokoyama A, Kohno N, Hirasawa Y et al. Evaluation of soluble IL-6 receptor concentration in serum and epithelial lining fluid from patients with interstitial lung diseases. Clin. Exp. Immunol. 1995; 100: 325 9.
- 23 Dore P, Lelievre E, Morel F et al. IL-6 and soluble IL-6 receptors (sIL-6R and sgp130) in human pleural effusions: Massive IL-6 production independently of underlying diseases. Clin. Exp. Immunol. 1997; 107: 182 8.
- 24 Mitsuyama K, Toyonaga A, Sasaki E et al. Soluble interleukin-6 receptors in inflammatory bowel disease: Relation to circulating interleukin-6. Gut 1995; 36: 45 9.
- 25 Morson BC. Colour Atlas of Gastrointestinal Pathology. London: Harvey Miller, 1988.
- 26
Harvey RF &
Bradshaw JM.
A simple index of Crohn’s disease activity.
Lancet
1980; i: 514.
10.1016/S0140-6736(80)92767-1 Google Scholar
- 27 Sandborn WJ, Tremaine WJ, Schroeder KW et al. Cyclosporin enemas for treatment-resistant, mildly to moderately active, left-sided ulcerative colitis. Am. J. Gastroenterol. 1993; 88: 640 5.
- 28 Ina K, Kusugami K, Yamaguchi T et al. Mucosal interleukin-8 is involved in neutrophil migration and binding to extracellular matrix in inflammatory bowel disease. Am. J. Gastroenterol. 1997; 92: 1342 6.
- 29 Peterson GL. A simplification of the protein assay method of Lowry et al. which is more generally applicable. Anal. Biochem. 1977; 83: 346 56.
- 30 Shinoda M, Haruta J, Tanimoto M et al. Lamina propria mononuclear cells express and respond to interleukin-2 differently in Crohn’s disease and ulcerative colitis. Intern. Med. 1996; 35: 679 85.
- 31 Yamamura M, Uyemura K, Deans RJ et al. Defining protective responses to pathogens: Cytokine profiles in leprosy lesions. Science 1991; 254: 277 9.
- 32 Riley SA, Mani V, Goodman MJ, Herd ME, Dutt S, Turnberg LA. Comparison of delayed release 5-aminosalicylic acid (mesalazine) and sulphasalazine in the treatment of mild to moderate ulcerative colitis relapse. Gut 1998; 29: 669 74.
- 33 Benedetti RD, Massa M, Pignatti P, Albani S, Novick D, Martini A. Serum soluble interleukin 6 (IL-6) receptor and IL-6/soluble IL-6 receptor complex in systemic juvenile rheumatoid arthritis. J. Clin. Invest 1994; 93: 2114 19.
- 34 Schreiber S, McDermott RP, Raedler A et al. Increased activation of isolated intestinal lamina propria mononuclear cells in inflammatory bowel disease. Gastroenterology 1991; 101: 1020 30.
- 35 Haruta J, Kusugami K, Kuroiwa A et al. Phenotypic and functional analysis of lamina propria mononuclear cells from colonoscopic biopsy specimens in patients with ulcerative colitis. Am. J. Gastroenterol. 1992; 87: 448 54.
- 36 Allison MC, Poulter LW, Dhillon AP, Pounder RE. Immunohistological studies of surface antigen on colonic lymphoid cells in normal and inflamed mucosa. Comparison of follicular and lamina propria lymphocytes. Gastroenterology 1990; 99: 421 30.
- 37 Narazaki M, Yasukawa K, Saito T et al. Soluble forms of the interleukin-6 signal-transducing receptor component gp130 in human serum possessing a potential to inhibit signals through membrane-anchored gp130. Blood 1993; 82: 1120 6.
- 38 Taga T, Hibi M, Murakami M et al. Interleukin-6 receptor and signals. Chem. Immunol. 1992; 51: 181 204.
- 39 Nakajima T, Yamamoto S, Cheng M et al. Soluble interleukin-6 receptor is released from receptor-bearing cell lines in vivo. Jpn. J. Cancer Res. 1992; 83: 373 8.
- 40 Malizia G, Calabrese A, Cottone M et al. Expression of leukocyte adhesion molecules by mucosal mononuclear phagocytes in inflammatory bowel disease. Gastroenterology 1991; 100: 150 9.
- 41 Cappello M, Keshav S, Prince C, Jewell DP, Gordon S. Detection of mRNAs for macrophage products in inflammatory bowel disease by in situ hybridisation. Gut 1992; 33: 1214 19.
- 42 Grimm MC, Elsbury SKO, Pavli P et al. Interleukin-8: Cells of origin in inflammatory bowel disease. Gut 1996; 38: 90 8.
- 43 Sakai T, Kusugami K, Nishimura H et al. Interleukin-15 activity in the rectal mucosa of inflammatory bowel disease. Gastroenterology 1998; 114: 1 8.
- 44 Mullin GE, Lazenby AJ, Harris ML, Bayless TM, James SP. Increased interleukin-2 messenger RNA in the intestinal mucosal lesions of Crohn’s disease but not ulcerative colitis. Gastroenterology 1992; 102: 1620 7.
- 45 Breese E, Braegger CP, Corrigan CJ, Walker-Smith JA, MacDonald TT. Interleukin-2- and interferon-γ-secreting T cells in normal and diseased human intestinal mucosa. Immunology 1993; 78: 127 34.
- 46 Matsuura T, West GA, Klein JS, Ferraris L, Fiocchi C. Soluble interleukin-2 and CD8 and CD4 receptors in inflammatory bowel disease. Gastroenterology 1992; 102: 2006 14.
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