Dual Effects of IL-1 Overactivity on the Immune System in a Mouse Model of Arthritis due to Deficiency of IL-1 Receptor Antagonist

Jian Yan^a,
Yan Jiao^{b, c},
Hong Chen^d,
Feng Jiao^b,
Karen A. Hasty^{b, e},
John M. Stuart^{a, e},
Weikuan Gu^{b
, ,}

a.
Department of Medicine, University of Tennessee Health Science Center, Memphis 38163, USA
b.
Department of Orthopedic Surgery and BME, University of Tennessee Health Science Center, Memphis 38163, USA
c.
Mudanjiang Medical College, Mudanjiang 157001, China
d.
The First Hospital of Qiqihaer City, Qiqihaer 161005, China
e.
Department of Veterans Affairs Medical Center, Memphis 38104, USA

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Corresponding author: E-mail address: wgu@uthsc.edu (Weikuan Gu)

摘要

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Abstract: Previous studies have revealed the significance of cytokine interleukin 1 (IL-1) in the onset and progression of rheumatoid arthritis (RA). The precise molecular mechanisms related to IL-1 underlying RA is still elusive. We conducted a whole genome-wide transcriptomal comparison of wild-type (WT) and arthritis-prone IL-1 receptor antagonist (IL-1rn) deficient BALB/c mice to address this issue. To refine our search efforts, gene expression profiling was also performed on paired wild-type and arthritis-resistant IL-1rn deficient DBA/1 mice as internal controls when identifying causative arthritis candidate genes. Two hundred and fifteen transcripts were found to be dysregulated greater than or equal to 2-fold in the diseased mice. The altered transcriptome in BALB/c mice revealed increased myeloid cell activities and impaired lymphocyte functionality, suggesting dual regulatory effects of IL-1 hyperactivity on immunological changes associated with arthritis development. Phase-specific gene expression changes were identified, such as early increase and late decrease of heat shock protein coding genes. Moreover, common gene expression changes were also observed, especially the upregulation of paired Ig-like receptor A (Pira) in both early and late phases of arthritis. Real-time PCR was performed to validate the expression of Pira and an intervention experiment with a major histocompatibility complex (MHC) class I inhibitor (brefeldin A) was carried out to investigate the role of suppressing Pira activity. We conclude that global pattern changes of common and distinct gene expressions may represent novel opportunities for better control of RA through early diagnosis and development of alternative therapeutic strategies.
- Arthritis /
- Gene expression /
- Mouse /
- Transcriptome

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参考文献(33)

[1]	Arend, W.P. Interleukin 1 receptor antagonist. A new member of the interleukin 1 family J. Clin. Invest., 88 (1991),pp. 1445-1451
[2]	Brunet de la Grange, P., Armstrong, F., Duval, V. et al. Low SCL/TAL1 expression reveals its major role in adult hematopoietic myeloid progenitors and stem cells Blood, 108 (2006),pp. 2998-3004
[3]	, Sherman, B.T., Hosack, D.A., Yang, J. et al. DAVID: Database for Annotation, Visualization, and Integrated Discovery Genome Biol., 4 (2003),p. R60
[4]	Devauchelle, V., Marion, S., Cagnard, N. et al. DNA microarray allows molecular profiling of rheumatoid arthritis and identification of pathophysiological targets Genes Immun., 5 (2004),pp. 597-608
[5]	Dinarello, C.A., Wolff, S.M. The role of interleukin-1 in disease N. Engl. J. Med., 328 (1993),pp. 106-113
[6]	Ericsson, A., Schalling, M., McIntyre, K.R. et al. Detection of neuropeptide Y and its mRNA in megakaryocytes: enhanced levels in certain autoimmune mice Proc. Natl. Acad. Sci. USA, 84 (1987),pp. 5585-5589
[7]	Freson, K., Thys, C., Wittewrongel, C. et al. Molecular cloning and characterization of the GATA1 cofactor human FOG1 and assessment of its binding to GATA1 proteins carrying D218 substitutions Hum. Genet., 112 (2003),pp. 42-49
[8]	Fujikado, N., Saijo, S., Iwakura, Y. Identification of arthritis-related gene clusters by microarray analysis of two independent mouse models for rheumatoid arthritis Arthritis Res. Ther., 8 (2006),p. R100
[9]	Hirota, K., Hashimoto, M., Yoshitomi, H. et al. J. Exp. Med., 204 (2007),pp. 41-47
[10]	Horai, R., Nakajima, A., Habiro, K. et al. TNF-alpha is crucial for the development of autoimmune arthritis in IL-1 receptor antagonist-deficient mice J. Clin. Invest., 114 (2004),pp. 1603-1611
[11]	Horai, R., Saijo, S., Tanioka, H. et al. Development of chronic inflammatory arthropathy resembling rheumatoid arthritis in interleukin 1 receptor antagonist-deficient mice J. Exp. Med., 191 (2000),pp. 313-320
[12]	Huynh, O.A., Hampartzoumian, T., Arm, J.P. et al. Down-regulation of leucocyte immunoglobulin-like receptor expression in the synovium of rheumatoid arthritis patients after treatment with disease-modifying anti-rheumatic drugs Rheumatology (Oxford), 46 (2007),pp. 742-751
[13]	Leek, J.T., Monsen, E., Dabney, A.R. et al. EDGE: extraction and analysis of differential gene expression Bioinformatics, 22 (2006),pp. 507-508
[14]	Lohr, J., Knoechel, B., Wang, J.J. et al. Role of IL-17 and regulatory T lymphocytes in a systemic autoimmune disease J. Exp. Med., 203 (2006),pp. 2785-2791
[15]	Nakae, S., Saijo, S., Horai, R. et al. IL-17 production from activated T cells is required for the spontaneous development of destructive arthritis in mice deficient in IL-1 receptor antagonist Proc. Natl. Acad. Sci. USA, 100 (2003),pp. 5986-5990
[16]	Niki, Y., Yamada, H., Seki, S. et al. Macrophage- and neutrophil-dominant arthritis in human IL-1 α transgenic mice J. Clin. Invest., 107 (2001),pp. 1127-1135
[17]	Pereira, S., Zhang, H., Takai, T. et al. The inhibitory receptor PIR-B negatively regulates neutrophil and macrophage integrin signaling J. Immunol., 173 (2004),pp. 5757-5765
[18]	Sakaguchi, S., Sakaguchi, N. Animal models of arthritis caused by systemic alteration of the immune system Curr. Opin. Immunol., 17 (2005),pp. 589-594
[19]	Sims, N.A., Green, J.R., Glatt, M. et al. Targeting osteoclasts with zoledronic acid prevents bone destruction in collagen-induced arthritis Arthritis Rheum., 50 (2004),pp. 2338-2346
[20]	Sternberg, E.M. Neural regulation of innate immunity: a coordinated nonspecific host response to pathogens Nat. Rev. Immunol., 6 (2006),pp. 318-328
[21]	Su, A.I., Cooke, M.P., Ching, K.A. et al. Large-scale analysis of the human and mouse transcriptomes Proc. Natl. Acad. Sci. USA, 99 (2002),pp. 4465-4470
[22]	Sunahori, K., Yamamura, M., Yamana, J. et al. The S100A8/A9 heterodimer amplifies proinflammatory cytokine production by macrophages via activation of nuclear factor kappa B and p38 mitogen-activated protein kinase in rheumatoid arthritis Arthritis Res. Ther., 8 (2006),p. R69
[23]	Sundar, S.K., Becker, K.J., Cierpial, M.A. et al. Intracerebroventricular infusion of interleukin 1 rapidly decreases peripheral cellular immune responses Proc. Natl. Acad. Sci. USA, 86 (1989),pp. 6398-6402
[24]	Sundar, S.K., Cierpial, M.A., Kilts, C. et al. Brain IL-1-induced immunosuppression occurs through activation of both pituitary-adrenal axis and sympathetic nervous system by corticotropin-releasing factor J. Neurosci., 10 (1990),pp. 3701-3706
[25]	Takai, T. A novel recognition system for MHC class I molecules constituted by PIR Adv. Immunol., 88 (2005),pp. 161-192
[26]	Takao, T., Hashimoto, K., De Souza, E.B. Modulation of interleukin-1 receptors in the brain-endocrine-immune axis by stress and infection Brain Behav. Immun., 9 (1995),pp. 276-291
[27]	Tedla, N., Gibson, K., McNeil, H.P. et al. The co-expression of activating and inhibitory leukocyte immunoglobulin-like receptors in rheumatoid synovium Am. J. Pathol., 160 (2002),pp. 425-431
[28]	Uehara, T., Blery, M., Kang, D.W. et al. Inhibition of IgE-mediated mast cell activation by the paired Ig-like receptor PIR-B J. Clin. Invest., 108 (2001),pp. 1041-1050
[29]	van der Pouw Kraan, T.C., van Gaalen, F.A., Huizinga, T.W. et al. Discovery of distinctive gene expression profiles in rheumatoid synovium using cDNA microarray technology: evidence for the existence of multiple pathways of tissue destruction and repair Genes Immun., 4 (2003),pp. 187-196
[30]	van Eden, W., van der Zee, R., Prakken, B. Heat-shock proteins induce T-cell regulation of chronic inflammation Nat. Rev. Immunol., 5 (2005),pp. 318-330
[31]	Vitkovic, L., Bockaert, J., Jacque, C. “Inflammatory” cytokines: neuromodulators in normal brain? J. Neurochem., 74 (2000),pp. 457-471
[32]	Wheway, J., Mackay, C.R., Newton, R.A. et al. A fundamental bimodal role for neuropeptide Y1 receptor in the immune system J. Exp. Med., 202 (2005),pp. 1527-1538
[33]	Yewdell, J.W., Bennink, J.R. Brefeldin A specifically inhibits presentation of protein antigens to cytotoxic T lymphocytes Science, 244 (1989),pp. 1072-1075