Abstract
Background: Sarcoidosis is a systemic granulomatous disorder of unknown origin. Lymphocytic inflammation is dominated by expression of Th1 type cytokines such as tumour necrosis factor α (TNFα). Interleukin 13 (IL-13) is a Th2 cytokine which is expressed by CD4+ T cells and has been shown to suppress TNFα in human blood monocytes. The role of IL-13 as a possible anti-inflammatory cytokine in sarcoidosis was investigated.
Methods: mRNA expression of IL-13, IL-4, IL-10, and TNFα in bronchoalveolar lavage (BAL) fluid cells and peripheral mononuclear blood cells (PBM) of 18 patients with sarcoidosis and nine healthy controls was assessed using RT-PCR. In addition, IL-13 protein levels in BAL cell culture supernatants from 12 patients and all controls were measured and immunocytochemistry of IL-13 protein was performed in BAL fluid cells of eight patients. TNFα concentrations were measured with and without stimulation with recombinant human (rh) IL-13, rhIL-10, and lipopolysaccharide (LPS).
Results: IL-13 mRNA expression was significantly increased in BAL cells and PBM of patients compared with controls (p<0.05). No significant difference was found in IL-4 mRNA or IL-10 mRNA expression in BAL fluid cells or PBM between the two groups. TNFα mRNA expression was significantly higher in BAL fluid cells of patients than controls (p<0.05). IL-13 protein levels in BAL cell culture supernatants were slightly raised in half the patients investigated but in only two controls. Immunocytochemistry detected IL-13 protein in alveolar macrophages of patients. IL-13 led to decreased TNFα concentrations (p<0.05).
Conclusions: IL-13 expression is increased in BAL cells and PBM in sarcoidosis and IL-13 is secreted from BAL cells. Alveolar macrophages may be the cellular source. These data suggest that IL-13 might have an anti-inflammatory effect by acting on TNFα.
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Selected References
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- Armstrong L., Foley N. M., Millar A. B. Inter-relationship between tumour necrosis factor-alpha (TNF-alpha) and TNF soluble receptors in pulmonary sarcoidosis. Thorax. 1999 Jun;54(6):524–530. doi: 10.1136/thx.54.6.524. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Baughman R. P., Strohofer S. A., Buchsbaum J., Lower E. E. Release of tumor necrosis factor by alveolar macrophages of patients with sarcoidosis. J Lab Clin Med. 1990 Jan;115(1):36–42. [PubMed] [Google Scholar]
- Bingisser R., Speich R., Zollinger A., Russi E., Frei K. Interleukin-10 secretion by alveolar macrophages and monocytes in sarcoidosis. Respiration. 2000;67(3):280–286. doi: 10.1159/000029511. [DOI] [PubMed] [Google Scholar]
- Bogdan C., Vodovotz Y., Nathan C. Macrophage deactivation by interleukin 10. J Exp Med. 1991 Dec 1;174(6):1549–1555. doi: 10.1084/jem.174.6.1549. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Cosentino G., Soprana E., Thienes C. P., Siccardi A. G., Viale G., Vercelli D. IL-13 down-regulates CD14 expression and TNF-alpha secretion in normal human monocytes. J Immunol. 1995 Sep 15;155(6):3145–3151. [PubMed] [Google Scholar]
- Edmondstone W. M., Wilson A. G. Sarcoidosis in Caucasians, Blacks and Asians in London. Br J Dis Chest. 1985 Jan;79(1):27–36. doi: 10.1016/0007-0971(85)90004-x. [DOI] [PubMed] [Google Scholar]
- Hancock A., Armstrong L., Gama R., Millar A. Production of interleukin 13 by alveolar macrophages from normal and fibrotic lung. Am J Respir Cell Mol Biol. 1998 Jan;18(1):60–65. doi: 10.1165/ajrcmb.18.1.2627. [DOI] [PubMed] [Google Scholar]
- Hino T., Nakamura H., Shibata Y., Abe S., Kato S., Tomoike H. Elevated levels of type II soluble tumor necrosis factor receptors in the bronchoalveolar lavage fluids of patients with sarcoidosis. Lung. 1997;175(3):187–193. doi: 10.1007/pl00007566. [DOI] [PubMed] [Google Scholar]
- Homolka J., Müller-Quernheim J. Increased interleukin 6 production by bronchoalveolar lavage cells in patients with active sarcoidosis. Lung. 1993;171(3):173–183. doi: 10.1007/BF00183946. [DOI] [PubMed] [Google Scholar]
- Lee C. G., Homer R. J., Zhu Z., Lanone S., Wang X., Koteliansky V., Shipley J. M., Gotwals P., Noble P., Chen Q. Interleukin-13 induces tissue fibrosis by selectively stimulating and activating transforming growth factor beta(1). J Exp Med. 2001 Sep 17;194(6):809–821. doi: 10.1084/jem.194.6.809. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Limper A. H., Colby T. V., Sanders M. S., Asakura S., Roche P. C., DeRemee R. A. Immunohistochemical localization of transforming growth factor-beta 1 in the nonnecrotizing granulomas of pulmonary sarcoidosis. Am J Respir Crit Care Med. 1994 Jan;149(1):197–204. doi: 10.1164/ajrccm.149.1.8111583. [DOI] [PubMed] [Google Scholar]
- Minshall E. M., Tsicopoulos A., Yasruel Z., Wallaert B., Akoum H., Vorng H., Tonnel A. B., Hamid Q. Cytokine mRNA gene expression in active and nonactive pulmonary sarcoidosis. Eur Respir J. 1997 Sep;10(9):2034–2039. doi: 10.1183/09031936.97.10092034. [DOI] [PubMed] [Google Scholar]
- Moller D. R., Forman J. D., Liu M. C., Noble P. W., Greenlee B. M., Vyas P., Holden D. A., Forrester J. M., Lazarus A., Wysocka M. Enhanced expression of IL-12 associated with Th1 cytokine profiles in active pulmonary sarcoidosis. J Immunol. 1996 Jun 15;156(12):4952–4960. [PubMed] [Google Scholar]
- Nakayama T., Hashimoto S., Amemiya E., Horie T. Elevation of plasma-soluble tumour necrosis factor receptors (TNF-R) in sarcoidosis. Clin Exp Immunol. 1996 May;104(2):318–324. doi: 10.1046/j.1365-2249.1996.13702.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Nowak D., Kanzow G., Magnussen H. Patienten mit Sarkoidose haben gehäuft eine bronchiale Hyperreaktivität. Pneumologie. 1990 Feb;44 (Suppl 1):572–573. [PubMed] [Google Scholar]
- Pinkston P., Bitterman P. B., Crystal R. G. Spontaneous release of interleukin-2 by lung T lymphocytes in active pulmonary sarcoidosis. N Engl J Med. 1983 Apr 7;308(14):793–800. doi: 10.1056/NEJM198304073081401. [DOI] [PubMed] [Google Scholar]
- Prasse A., Georges C. G., Biller H., Hamm H., Matthys H., Luttmann W., Virchow J. C., Jr Th1 cytokine pattern in sarcoidosis is expressed by bronchoalveolar CD4+ and CD8+ T cells. Clin Exp Immunol. 2000 Nov;122(2):241–248. doi: 10.1046/j.1365-2249.2000.01365.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Punnonen J., Aversa G., Cocks B. G., McKenzie A. N., Menon S., Zurawski G., de Waal Malefyt R., de Vries J. E. Interleukin 13 induces interleukin 4-independent IgG4 and IgE synthesis and CD23 expression by human B cells. Proc Natl Acad Sci U S A. 1993 Apr 15;90(8):3730–3734. doi: 10.1073/pnas.90.8.3730. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Pène J., Rousset F., Brière F., Chrétien I., Bonnefoy J. Y., Spits H., Yokota T., Arai N., Arai K., Banchereau J. IgE production by normal human lymphocytes is induced by interleukin 4 and suppressed by interferons gamma and alpha and prostaglandin E2. Proc Natl Acad Sci U S A. 1988 Sep;85(18):6880–6884. doi: 10.1073/pnas.85.18.6880. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Roberge F. G., de Smet M. D., Benichou J., Kriete M. F., Raber J., Hakimi J. Treatment of uveitis with recombinant human interleukin-13. Br J Ophthalmol. 1998 Oct;82(10):1195–1198. doi: 10.1136/bjo.82.10.1195. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Robinson B. W., McLemore T. L., Crystal R. G. Gamma interferon is spontaneously released by alveolar macrophages and lung T lymphocytes in patients with pulmonary sarcoidosis. J Clin Invest. 1985 May;75(5):1488–1495. doi: 10.1172/JCI111852. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Salez F., Gosset P., Copin M. C., Lamblin Degros C., Tonnel A. B., Wallaert B. Transforming growth factor-beta1 in sarcoidosis. Eur Respir J. 1998 Oct;12(4):913–919. doi: 10.1183/09031936.98.12040913. [DOI] [PubMed] [Google Scholar]
- Shigehara K., Shijubo N., Hirasawa M., Abe S., Uede T. Immunolocalization of extracellular matrix proteins and integrins in sarcoid lymph nodes. Virchows Arch. 1998 Jul;433(1):55–61. doi: 10.1007/s004280050216. [DOI] [PubMed] [Google Scholar]
- Steffen M., Petersen J., Oldigs M., Karmeier A., Magnussen H., Thiele H. G., Raedler A. Increased secretion of tumor necrosis factor-alpha, interleukin-1-beta, and interleukin-6 by alveolar macrophages from patients with sarcoidosis. J Allergy Clin Immunol. 1993 Apr;91(4):939–949. doi: 10.1016/0091-6749(93)90352-g. [DOI] [PubMed] [Google Scholar]
- Thomas P. D., Hunninghake G. W. Current concepts of the pathogenesis of sarcoidosis. Am Rev Respir Dis. 1987 Mar;135(3):747–760. doi: 10.1164/arrd.1987.135.3.747. [DOI] [PubMed] [Google Scholar]
- Watson M. L., White A. M., Campbell E. M., Smith A. W., Uddin J., Yoshimura T., Westwick J. Anti-inflammatory actions of interleukin-13: suppression of tumor necrosis factor-alpha and antigen-induced leukocyte accumulation in the guinea pig lung. Am J Respir Cell Mol Biol. 1999 May;20(5):1007–1012. doi: 10.1165/ajrcmb.20.5.3540. [DOI] [PubMed] [Google Scholar]
- Wills-Karp M., Luyimbazi J., Xu X., Schofield B., Neben T. Y., Karp C. L., Donaldson D. D. Interleukin-13: central mediator of allergic asthma. Science. 1998 Dec 18;282(5397):2258–2261. doi: 10.1126/science.282.5397.2258. [DOI] [PubMed] [Google Scholar]
- Zhu Z., Homer R. J., Wang Z., Chen Q., Geba G. P., Wang J., Zhang Y., Elias J. A. Pulmonary expression of interleukin-13 causes inflammation, mucus hypersecretion, subepithelial fibrosis, physiologic abnormalities, and eotaxin production. J Clin Invest. 1999 Mar;103(6):779–788. doi: 10.1172/JCI5909. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Zissel G., Homolka J., Schlaak J., Schlaak M., Müller-Quernheim J. Anti-inflammatory cytokine release by alveolar macrophages in pulmonary sarcoidosis. Am J Respir Crit Care Med. 1996 Sep;154(3 Pt 1):713–719. doi: 10.1164/ajrccm.154.3.8810610. [DOI] [PubMed] [Google Scholar]
- de Vries J. E. Molecular and biological characteristics of interleukin-13. Chem Immunol. 1996;63:204–218. [PubMed] [Google Scholar]
- de Vries J. E. The role of IL-13 and its receptor in allergy and inflammatory responses. J Allergy Clin Immunol. 1998 Aug;102(2):165–169. doi: 10.1016/s0091-6749(98)70080-6. [DOI] [PubMed] [Google Scholar]
- de Waal Malefyt R., Haanen J., Spits H., Roncarolo M. G., te Velde A., Figdor C., Johnson K., Kastelein R., Yssel H., de Vries J. E. Interleukin 10 (IL-10) and viral IL-10 strongly reduce antigen-specific human T cell proliferation by diminishing the antigen-presenting capacity of monocytes via downregulation of class II major histocompatibility complex expression. J Exp Med. 1991 Oct 1;174(4):915–924. doi: 10.1084/jem.174.4.915. [DOI] [PMC free article] [PubMed] [Google Scholar]
