Altered AKT1 and MAPK1 Gene Expression on Peripheral Blood Mononuclear Cells and Correlation with T-Helper-Transcription Factors in Systemic Lupus Erythematosus Patients
Kinases have been implicated in the immunopathological mechanisms of Systemic Lupus Erythematosus (SLE). v-akt murine-thymoma viral-oncogene-homolog 1 (AKT1) and mitogen-activated-protein-kinase 1 (MAPK1) gene expressions in peripheral mononuclear cells from thirteen SLE patients with inactive or mild disease were evaluated using quantitative real-time reverse-transcription polymerase-chain-reaction and analyzed whether there was any correlation with T-helper (Th) transcription factors (TF) gene expression, cytokines, and S100A8/S100A9-(Calprotectin). Age- and gender-matched thirteen healthy controls were examined. AKT1 and MAPK1 expressions were upregulated in SLE patients and correlated with Th17-(Retinoic acid-related orphan receptor (ROR)-C), T-regulatory-(Treg)-(Transforming Growth Factor Beta (TGFB)-2), and Th2-(interleukin (IL)-5)-related genes. MAPK1 expression correlated with Th1-(IL-12A, T-box TF-(T-bet)), Th2-(GATA binding protein-(GATA)-3), and IL-10 expressions. IL-10 expression was increased and correlated with plasma Tumor Necrosis Factor (TNF)-α and Th0-(IL-2), Th1-(IL-12A, T-bet), GATA3, Treg-(Forkhead/winged-helix transcription factor- (FOXP)-3), and IL-6 expressions. FOXP3 expression, FOXP3/RORC, and FOXP3/GATA3 expression ratios were increased. Plasma IL-1β, IL-12(p70), Interferon-(IFN)-γ, and IL-6 cytokines were augmented. Plasma IL-1β, IL-6, IL-2, IFN-γ, TNF-α, IL-10, and IL-13 correlated with C-reactive protein, respectively. Increased Calprotectin correlated with neutrophils. Conclusion, SLE patients presented a systemic immunoinflammatory activity, augmented AKT1 and MAPK1 expressions, proinflammatory cytokines, and Calprotectin, together with increased expression of Treg-related genes, suggesting a regulatory feedback opposing the inflammatory activity. 1. Introduction Systemic Lupus Erythematosus (SLE) is a chronic inflammatory autoimmune disease most common in women of reproductive age [1], characterized by a relapsing/remitting course and the involvement of multiple organs, including skin, kidneys, and central nervous system. Pathophysiologically is characterized by the dysfunction of T, B, and dendritic cells (DC), skewed cytokine production, breakdown of immunological tolerance, and by the production of antinuclear autoantibodies [2–5]. In SLE bone marrow mononuclear cells, Nakou et al. [6] identified central gene regulators implicated in disease pathogenesis which include activation of multiple kinase pathways (MAPK/extracellular regulated MAP kinase (ERK), Signal Transducer and Activator of Transcription (STAT), AKT, and
References
[1]
R. Cervera, “Systemic lupus erythematosus in Europe at the change of the millennium: lessons from the ‘Euro-Lupus Project’,” Autoimmunity Reviews, vol. 5, no. 3, pp. 180–186, 2006.
[2]
A. Perl, “Pathogenic mechanisms in systemic lupus erythematosus,” Autoimmunity, vol. 43, no. 1, pp. 1–6, 2010.
[3]
S. A. Jenks and I. Sanz, “Altered B cell receptor signaling in human systemic lupus erythematosus,” Autoimmunity Reviews, vol. 8, no. 3, pp. 209–213, 2009.
[4]
J. C. Crispín, V. C. Kyttaris, C. Terhorst, and G. C. Tsokos, “T cells as therapeutic targets in SLE,” Nature Reviews Rheumatology, vol. 6, no. 6, pp. 317–325, 2010.
[5]
G. C. Tsokos, “Systemic lupus erythematosus,” The New England Journal of Medicine, vol. 365, pp. 2110–2121, 2011.
[6]
M. Nakou, G. Bertsias, I. Stagakis et al., “Gene network analysis of bone marrow mononuclear cells reveals activation of multiple kinase pathways in human systemic lupus erythematosus,” PLoS ONE, vol. 5, no. 10, Article ID e13351, 2010.
[7]
M. M. Juntilla and G. A. Koretzky, “Critical roles of the PI3K/Akt signaling pathway in T cell development,” Immunology Letters, vol. 116, no. 2, pp. 104–110, 2008.
[8]
D. Finlay and D. A. Cantrell, “Metabolism, migration and memory in cytotoxic T cells,” Nature Reviews Immunology, vol. 11, no. 2, pp. 109–117, 2011.
[9]
A. Bononi, C. Agnoletto, E. De Marchi, et al., “Protein kinases and phosphatases in the control of cell fate,” Enzyme Research, vol. 2011, Article ID 329098, 26 pages, 2011.
[10]
A. N. Macintyre, D. Finlay, G. Preston et al., “Protein kinase B controls transcriptional programs that direct cytotoxic T cell fate but is dispensable for T cell metabolism,” Immunity, vol. 34, no. 2, pp. 224–236, 2011.
[11]
T. E. Taher, K. Parikh, F. Flores-Borja et al., “Protein phosphorylation and kinome profiling reveal altered regulation of multiple signaling pathways in B lymphocytes from patients with systemic lupus erythematosus,” Arthritis and Rheumatism, vol. 62, no. 8, pp. 2412–2423, 2010.
[12]
G. Gorelik and B. Richardson, “Key role of ERK pathway signaling in lupus,” Autoimmunity, vol. 43, no. 1, pp. 17–22, 2010.
[13]
Y. Molad, M. Amit-Vasina, O. Bloch, E. Yona, and M. J. Rapoport, “Increased ERK and JNK activities correlate with disease activity in patients with systemic lupus erythematosus,” Annals of the Rheumatic Diseases, vol. 69, no. 1, pp. 175–180, 2010.
[14]
A. H. Sawalha, M. Jeffries, R. Webb et al., “Defective T-cell ERK signaling induces interferon-regulated gene expression and overexpression of methylation-sensitive genes similar to lupus patients,” Genes and Immunity, vol. 9, no. 4, pp. 368–378, 2008.
[15]
S. Krishnan, Y. T. Juang, B. Chowdhury et al., “Differential expression and molecular associations of Syk in systemic lupus erythematosus T cells,” Journal of Immunology, vol. 181, no. 11, pp. 8145–8152, 2008.
[16]
S. A. Apostolidis, L. A. Lieberman, K. Kis-Toth, et al., “The dysregulation of cytokine networks in systemic lupus erythematosus,” Journal of Interferon & Cytokine Research, vol. 31, pp. 769–779, 2011.
[17]
N. Jacob and W. Stohl , “Cytokine disturbances in systemic lupus erythematosus,” Arthritis Research & Therapy, vol. 13, article 228, 2011.
[18]
S. N. Kariuki and T. B. Niewold, “Genetic regulation of serum cytokines in systemic lupus erythematosus,” Translational Research, vol. 155, no. 3, pp. 109–117, 2010.
[19]
D. L. Su, Z. M. Lu, M. N. Shen, et al., “Roles of pro- and anti-inflammatory cytokines in the pathogenesis of SLE,” Journal of Biomedicine and Biotechnology, vol. 2012, Article ID 347141, 15 pages, 2012.
[20]
S. L. Yu, W. P. Kuan, C. K. Wong, et al., “Immunopathological roles of cytokines, chemokines, signaling molecules, and pattern-recognition receptors in systemic lupus erythematosus,” Clinical and Developmental Immunology, vol. 2012, Article ID 715190, 14 pages, 2012.
[21]
J. Zhu and W. E. Paul, “Heterogeneity and plasticity of T helper cells,” Cell Research, vol. 20, no. 1, pp. 4–12, 2010.
[22]
S. Nakayamada, H. Takahashi, Y. Kanno, et al., “Helper T cell diversity and plasticity,” Current Opinion in Immunology, vol. 24, pp. 297–302, 2012.
[23]
R. W. Y. Chan, F. M. M. Lai, E. K. M. Li et al., “Imbalance of Th1/Th2 transcription factors in patients with lupus nephritis,” Rheumatology, vol. 45, no. 8, pp. 951–957, 2006.
[24]
S. Garcia-Rodriguez, S. Arias-Santiago, R. Perandres-Lopez, et al., “Increased gene expression of Toll-like receptor 4 on peripheral blood mononuclear cells in patients with psoriasis,” Journal of the European Academy of Dermatology and Venereology. In press.
[25]
B. H. Chung, H. J. Oh, S. G. Piao, et al., “Clinical significance of the ratio between FOXP3 positive regulatory T cell and interleukin-17 secreting cell in renal allograft biopsies with acute T-cell-mediated rejection,” Immunology, vol. 136, no. 3, pp. 344–351, 2012.
[26]
K. Miyake, M. Akahoshi, and H. Nakashima, “Th subset balance in lupus nephritis,” Journal of Biomedicine and Biotechnology, vol. 2011, Article ID 980286, 7 pages, 2011.
[27]
M. S. Soyfoo, J. Roth, T. Vogl, R. Pochet, and G. Decaux, “Phagocyte-specific S100A8/A9 protein levels during disease exacerbations and infections in systemic lupus erythematosus,” Journal of Rheumatology, vol. 36, no. 10, pp. 2190–2194, 2009.
[28]
C. Lood, M. Stenstr？m, H. Tydén et al., “Protein synthesis of the pro-inflammatory S100A8/A9 complex in plasmacytoid dendritic cells and cell surface S100A8/A9 on leukocyte subpopulations in systemic lupus erythematosus,” Arthritis Research and Therapy, vol. 13, no. 2, article R60, 2011.
[29]
E. J. Pavon, S. Garcia-Rodriguez, E. Zumaquero, et al., “Increased expression and phosphorylation of the two S100A9 isoforms in mononuclear cells from patients with systemic lupus erythematosus: a proteomic signature for circulating low-density granulocytes,” Journal of Proteomics, vol. 75, no. 6, pp. 1778–91, 2012.
[30]
C. Bombardier, D. D. Gladman, M. B. Urowitz, D. Caron, and C. H. Chang, “Derivation of the SLEDAI: a disease activity index for lupus patients,” Arthritis and Rheumatism, vol. 35, no. 6, pp. 630–640, 1992.
[31]
E. M. Tan, A. S. Cohen, and J. F. Fries, “The 1982 revised criteria for the classification of systemic lupus erythrematosus,” Arthritis and Rheumatism, vol. 25, no. 11, pp. 1271–1277, 1982.
[32]
K. J. Livak and T. D. Schmittgen, “Analysis of relative gene expression data using real-time quantitative PCR and the 2-ΔΔCT method,” Methods, vol. 25, no. 4, pp. 402–408, 2001.
[33]
J. Zhu and W. E. Paul, “Peripheral CD4+ T-cell differentiation regulated by networks of cytokines and transcription factors,” Immunological Reviews, vol. 238, no. 1, pp. 247–262, 2010.
[34]
J. B. Wing and S. Sakaguchi, “Multiple treg suppressive modules and their adaptability,” Frontiers in Immunology, vol. 3, p. 178, 2012.
[35]
H. J. Haga, J. G. Brun, H. B. Berntzen, R. Cervera, M. Khamashta, and G. R. V. Hughes, “Calprotection in patients with systemic lupus erythematosus: relation to clinical and laboratory parameters of disease activity,” Lupus, vol. 2, no. 1, pp. 47–50, 1993.
[36]
L. Wei, G. Vahedi, H. W. Sun et al., “Discrete roles of STAT4 and STAT6 transcription factors in tuning epigenetic modifications and transcription during T helper cell differentiation,” Immunity, vol. 32, no. 6, pp. 840–851, 2010.
[37]
R. J. Salmond, J. Emery, K. Okkenhaug, and R. Zamoyska, “MAPK, phosphatidylinositol 3-kinase, and mammalian target of rapamycin pathways converge at the level of ribosomal protein S6 phosphorylation to control metabolic signaling in CD8 T cells,” Journal of Immunology, vol. 183, no. 11, pp. 7388–7397, 2009.
[38]
Q. Wan, L. Kozhaya, A. ElHed, et al., “Cytokine signals through PI-3 kinase pathway modulate Th17 cytokine production by CCR6+ human memory T cells,” The Journal of Experimental Medicine, vol. 208, pp. 1875–1887, 2011.
[39]
Y. Kurebayashi, S. Nagai, A. Ikejiri, et al., “PI3K-Akt-mTORC1-S6K1/2 axis controls Th17 differentiation by regulating Gfi1 expression and nuclear translocation of RORgamma,” Cell Reports, vol. 1, pp. 360–373, 2012.
[40]
S. Sauer, L. Bruno, A. Hertweck et al., “T cell receptor signaling controls Foxp3 expression via PI3K, Akt, and mTOR,” Proceedings of the National Academy of Sciences of the United States of America, vol. 105, no. 22, pp. 7797–7802, 2008.
[41]
Y. Arimura, F. Shiroki, S. Kuwahara et al., “Akt is a neutral amplifier for Th cell differentiation,” The Journal of Biological Chemistry, vol. 279, no. 12, pp. 11408–11416, 2004.
[42]
K. Okkenhaug, D. T. Patton, A. Bilancio, F. Gar？on, W. C. Rowan, and B. Vanhaesebroeck, “The p110δ isoform of phosphoinositide 3-kinase controls clonal expansion and differentiation of Th cells,” Journal of Immunology, vol. 177, no. 8, pp. 5122–5128, 2006.
[43]
A. Suarez-Fueyo, D. F. Barber, J. Martinez-Ara, et al., “Enhanced phosphoinositide 3-kinase delta activity is a frequent event in systemic lupus erythematosus that confers resistance to activation-induced T cell death,” The Journal of Immunology, vol. 187, pp. 2376–2385, 2011.
[44]
J. Morel, R. Audo, M. Hahne, and B. Combe, “Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces rheumatoid arthritis synovial fibroblast proliferation through mitogen-activated protein kinases and phosphatidylinositol 3-kinase/Akt,” The Journal of Biological Chemistry, vol. 280, no. 16, pp. 15709–15718, 2005.
[45]
A. Komatsuda, H. Wakui, K. Iwamoto et al., “Up-regulation of TRAIL mRNA expression in peripheral blood mononuclear cells from patients with active systemic lupus erythematosus,” Clinical Immunology, vol. 125, no. 1, pp. 26–29, 2007.
[46]
S. C. Huang, H. F. Tsai, H. T. Tzeng, H. J. Liao, and P. N. Hsu, “Lipid raft assembly and LcK recruitment in TRAIL costimulation mediates NF-κB activation and T cell proliferation,” Journal of Immunology, vol. 186, no. 2, pp. 931–939, 2011.
[47]
A. M. Fischer, C. D. Katayama, G. Pagès, J. Pouysségur, and S. M. Hedrick, “The role of Erk1 and Erk2 in multiple stages of T cell development,” Immunity, vol. 23, no. 4, pp. 431–443, 2005.
[48]
A. von Kriegsheim, D. Baiocchi, M. Birtwistle et al., “Cell fate decisions are specified by the dynamic ERK interactome,” Nature Cell Biology, vol. 11, no. 12, pp. 1458–1464, 2009.
[49]
Y. Zhu and P. J. Bertics, “Chemoattractant-induced signaling via the Ras-ERK and PI3K-Akt networks, along with leukotriene C4 release, is dependent on the tyrosine kinase Lyn in IL-5- and IL-3-primed human blood eosinophils,” Journal of Immunology, vol. 186, no. 1, pp. 516–526, 2011.
[50]
D. Arasappan, W. Tong, P. Mummaneni, H. Fang, and S. Amur, “Meta-analysis of microarray data using a pathway-based approach identifies a 37-gene expression signature for systemic lupus erythematosus in human peripheral blood mononuclear cells,” BMC Medicine, vol. 9, article 65, 2011.
[51]
V. Gateva, J. K. Sandling, G. Hom et al., “A large-scale replication study identifies TNIP1, PRDM1, JAZF1, UHRF1BP1 and IL10 as risk loci for systemic lupus erythematosus,” Nature Genetics, vol. 41, no. 11, pp. 1228–1233, 2009.
[52]
M. O. Li and R. A. Flavell, “Contextual regulation of inflammation: a duet by transforming growth factor-β and interleukin-10,” Immunity, vol. 28, no. 4, pp. 468–476, 2008.
[53]
W. Ouyang, S. Rutz, N. K. Crellin, P. A. Valdez, and S. G. Hymowitz, “Regulation and functions of the IL-10 family of cytokines in inflammation and disease,” Annual Review of Immunology, vol. 29, pp. 71–109, 2011.
[54]
M. Saraiva and A. O'Garra, “The regulation of IL-10 production by immune cells,” Nature Reviews Immunology, vol. 10, no. 3, pp. 170–181, 2010.
[55]
N. A. Carter, R. Vasconcellos, E. C. Rosser et al., “Mice lacking endogenous IL-10-producing regulatory B cells develop exacerbated disease and present with an increased frequency of Th1/Th17 but a decrease in regulatory T cells,” Journal of Immunology, vol. 186, no. 10, pp. 5569–5579, 2011.
[56]
M. Saraiva, J. R. Christensen, M. Veldhoen, T. L. Murphy, K. M. Murphy, and A. O'Garra, “Interleukin-10 production by Th1 cells requires interleukin-12-induced STAT4 transcription factor and ERK MAP kinase activation by high antigen dose,” Immunity, vol. 31, no. 2, pp. 209–219, 2009.
[57]
L. R. Grant, Z. J. Yao, C. M. Hedrich et al., “Stat4-dependent, T-bet-independent regulation of IL-10 in NK cells,” Genes and Immunity, vol. 9, no. 4, pp. 316–327, 2008.
[58]
M. J. McGeachy, K. S. Bak-Jensen, Y. Chen et al., “TGF-β and IL-6 drive the production of IL-17 and IL-10 by T cells and restrain TH-17 cell-mediated pathology,” Nature Immunology, vol. 8, no. 12, pp. 1390–1397, 2007.
[59]
S. Avagyan, F. Aguilo-Payeras, K. Kamezaki, et al., “Quantitative trait mapping reveals a regulatory axis involving peroxisome proliferator-activated receptors, PRDM16, transforming growth factor-beta2 and FLT3 in hematopoiesis,” Blood, vol. 118, pp. 6078–6086, 2011.
[60]
A. L. Astier, G. Beriou, T. M. Eisenhaure, S. M. Anderton, D. A. Hafler, and N. Hacohen, “RNA interference screen in primary human T cells reveals FLT3 as a modulator of IL-10 levels,” Journal of Immunology, vol. 184, no. 2, pp. 685–693, 2010.
[61]
P. Lopez, C. Gutierrez, and A. Suarez, “IL-10 and TNFalpha genotypes in SLE,” Journal of Biomedicine and Biotechnology, vol. 2010, Article ID 838390, 2010.
[62]
T. Smallie, G. Ricchetti, N. J. Horwood, M. Feldmann, A. R. Clark, and L. M. Williams, “IL-10 inhibits transcription elongation of the human TNF gene in primary macrophages,” Journal of Experimental Medicine, vol. 207, no. 10, pp. 2081–2088, 2010.
[63]
M. Zubiaur, O. Fernández, E. Ferrero et al., “CD38 is associated with lipid rafts and upon receptor stimulation leads to Akt/protein kinase B and Erk activation in the absence of the CD3-ζ immune receptor tyrosine-based activation motifs,” Journal of Biological Chemistry, vol. 277, no. 1, pp. 13–22, 2002.
[64]
E. Zumaquero, P. Mu？oz, M. Cobo et al., “Exosomes from human lymphoblastoid B cells express enzymatically active CD38 that is associated with signaling complexes containing CD81, Hsc-70 and Lyn,” Experimental Cell Research, vol. 316, no. 16, pp. 2692–2706, 2010.
[65]
D. T. Patton, M. D. Wilson, W. C. Rowan, D. R. Soond, and K. Okkenhaug, “The PI3K p110δ regulates expression of CD38 on regulatory T cells,” PLoS ONE, vol. 6, no. 3, Article ID e17359, 2011.
[66]
P. A. Blair, L. Y. Nore？a, F. Flores-Borja et al., “CD19+ B cells exhibit regulatory capacity in healthy individuals but are functionally impaired in systemic lupus erythematosus patients,” Immunity, vol. 32, no. 1, pp. 129–140, 2010.
[67]
A. Chaudhry, R. M. Samstein, P. Treuting et al., “Interleukin-10 signaling in regulatory T cells is required for suppression of Th17 cell-mediated inflammation,” Immunity, vol. 34, no. 4, pp. 566–578, 2011.
[68]
S. Huber, N. Gagliani, E. Esplugues et al., “Th17 cells express interleukin-10 receptor and are controlled by Foxp3- and Foxp3+ regulatory CD4+ T cells in an interleukin-10-dependent manner,” Immunity, vol. 34, no. 4, pp. 554–565, 2011.
[69]
A. Y. Rudensky, “Regulatory T cells and Foxp3,” Immunological Reviews, vol. 241, no. 1, pp. 260–268, 2011.
[70]
M. Barreto, R. C. Ferreira, L. Louren？o et al., “Low frequency of CD4+CD25+ Treg in SLE patients: a heritable trait associated with CTLA4 and TGFβ gene variants,” BMC Immunology, vol. 10, article 5, 2009.
[71]
M. J. L. Suggs, V. Majithia, R. E. Lewis, and J. M. Cruse, “HLA DRB1*1503 allelic haplotype predominance and associated immunodysregulation in systemic lupus erythematosus,” Experimental and Molecular Pathology, vol. 91, no. 2, pp. 548–562, 2011.
[72]
N. A. Azab, I. H. Bassyouni, Y. Emad, G. A. Abd El-Wahab, G. Hamdy, and M. A. Mashahit, “CD4+CD25+ regulatory T cells (TREG) in Systemic Lupus Erythematosus (SLE) patients: the possible influence of treatment with corticosteroids,” Clinical Immunology, vol. 127, no. 2, pp. 151–157, 2008.
[73]
C. Prado, J. Gómez, P. López, B. de Paz, C. Gutiérrez, and A. Suárez, “Dexamethasone upregulates FOXP3 expression without increasing regulatory activity,” Immunobiology, vol. 216, no. 3, pp. 386–392, 2011.
[74]
S. Sbiera, T. Dexneit, S. D. Reichardt, et al., “Influence of short-term glucocorticoid therapy on regulatory T cells in vivo,” PLoS ONE, vol. 6, Article ID e24345, 2011.
[75]
W. H. Abdulahad, A. M. H. Boots, and C. G. M. Kallenberg, “FoxP3+ CD4+ T cells in systemic autoimmune diseases: the delicate balance between true regulatory T cells and effector Th-17 cells,” Rheumatology, vol. 50, no. 4, pp. 646–656, 2011.
[76]
K. M. Murphy and B. Stockinger, “Effector T cell plasticity: flexibility in the face of changing circumstances,” Nature Immunology, vol. 11, no. 8, pp. 674–680, 2010.
[77]
X. Valencia, C. Yarboro, G. Illei, and P. E. Lipsky, “Deficient CD4+ T regulatory cell function in patients with active systemic lupus erythematosus,” Journal of Immunology, vol. 178, no. 4, pp. 2579–2588, 2007.
[78]
J. Ma, J. Yu, X. Tao, L. Cai, J. Wang, and S. G. Zheng, “The imbalance between regulatory and IL-17-secreting CD4+ T cells in lupus patients,” Clinical Rheumatology, vol. 29, no. 11, pp. 1251–1258, 2010.
[79]
Q. Xing, B. Wang, H. Su, J. Cui, and J. Li, “Elevated Th17 cells are accompanied by FoxP3+ Treg cells decrease in patients with lupus nephritis,” Rheumatology International, vol. 32, no. 4, pp. 949–958, 2011.
[80]
S. Chapoval, P. Dasgupta, N. J. Dorsey, and A. D. Keegan, “Regulation of the T helper cell type 2 (Th2)/T regulatory cell (Treg) balance by IL-4 and STAT6,” Journal of Leukocyte Biology, vol. 87, no. 6, pp. 1011–1018, 2010.
[81]
Y. Wang, M. A. Su, and Y. Y. Wan, “An essential role of the transcription factor GATA-3 for the function of regulatory T cells,” Immunity, vol. 35, pp. 337–348, 2011.
[82]
K. Shah, W. W. Lee, S. H. Lee et al., “Dysregulated balance of Th17 and Th1 cells in systemic lupus erythematosus,” Arthritis Research and Therapy, vol. 12, no. 2, article R53, 2010.
[83]
F. Sallusto, E. Kremmer, B. Palermo, et al., “Switch in chemokine receptor expression upon TCR stimulation reveals novel homing potential for recently activated T cells,” European Journal of Immunology, vol. 29, pp. 2037–2045, 1999.
[84]
C. Prado, B. de Paz, J. Gomez, et al., “Glucocorticoids enhance Th17/Th1 imbalance and signal transducer and activator of transcription 3 expression in systemic lupus erythematosus patients,” Rheumatology, vol. 50, pp. 1794–1801, 2011.
[85]
D. A. Horwitz, “Identity of mysterious CD4+CD25-Foxp3+ cells in SLE,” Arthritis Research & Therapy, vol. 12, no. 1, p. 101, 2010.
[86]
X. Zhou, S. Bailey-Bucktrout, L. T. Jeker, and J. A. Bluestone, “Plasticity of CD4+ FoxP3+ T cells,” Current Opinion in Immunology, vol. 21, no. 3, pp. 281–285, 2009.
[87]
L. Lu, X. Zhou, J. Wang, S. G. Zheng, and D. A. Horwitz, “Characterization of protective human CD4CD25 FOXP3 regulatory T cells generated with IL-2, TGF-β and retinoic acid,” PloS ONE, vol. 5, no. 12, p. e15150, 2010.
[88]
M. B. Hale, P. O. Krutzik, S. S. Samra, J. M. Crane, and G. P. Nolan, “Stage dependent aberrant regulation of cytokine-STAT signaling in murine systemic lupus erythematosus,” PLoS ONE, vol. 4, no. 8, Article ID e6756, 2009.
[89]
H. Cash, M. Relle, J. Menke et al., “Interleukin 6 (IL-6) deficiency delays lupus nephritis in MRL-Fas lpr mice: the IL-6 pathway as a new therapeutic target in treatment of autoimmune kidney disease in systemic lupus erythematosus,” Journal of Rheumatology, vol. 37, no. 1, pp. 60–70, 2010.
[90]
H. Y. Chun, J. W. Chung, H. A. Kim et al., “Cytokine IL-6 and IL-10 as biomarkers in systemic lupus erythematosus,” Journal of Clinical Immunology, vol. 27, no. 5, pp. 461–466, 2007.
[91]
S. Hu, W. Xiao, F. Kong, D. Ke, R. Qin, and M. Su, “Regulatory T cells and their molecular markers in peripheral blood of the patients with systemic lupus erythematosus,” Journal of Huazhong University of Science and Technology, vol. 28, no. 5, pp. 549–552, 2008.
[92]
K. Ohl and K. Tenbrock, “Inflammatory cytokines in systemic lupus erythematosus,” Journal of Biomedicine and Biotechnology, vol. 2011, Article ID 432595, 14 pages, 2011.
[93]
A. Sabry, H. sheashaa, A. El-husseini et al., “Proinflammatory cytokines (TNF-α and IL-6) in Egyptian patients with SLE: its correlation with disease activity,” Cytokine, vol. 35, no. 3-4, pp. 148–153, 2006.
[94]
W. E. Naugler and M. Karin, “The wolf in sheep's clothing: the role of interleukin-6 in immunity, inflammation and cancer,” Trends in Molecular Medicine, vol. 14, no. 3, pp. 109–119, 2008.
[95]
E. Sonoda, R. Matsumoto, Y. Hitoshi et al., “Transforming growth factor β induces IgA production and acts additively with interleukin 5 for IgA production,” The Journal of Experimental Medicine, vol. 170, no. 4, pp. 1415–1420, 1989.
[96]
T. Hayashi, “Therapeutic strategies for SLE involving cytokines: mechanism-oriented therapies especially IFN-λ targeting gene therapy,” Journal of Biomedicine and Biotechnology, vol. 2010, Article ID 461641, 19 pages, 2010.
[97]
L. D. Erickson, T. M. Foy, and T. J. Waldschmidt, “Murine B1 B cells require IL-5 for optimal T cell-dependent activation,” Journal of Immunology, vol. 166, no. 3, pp. 1531–1539, 2001.
[98]
F. Martin and J. F. Kearney, “B-cell subsets and the mature preimmune repertoire. Marginal zone and B1 B cells as part of a ″natural immune memory″,” Immunological Reviews, vol. 175, pp. 70–79, 2000.
[99]
S. Koyasu and K. Moro, “Type 2 innate immune responses and the natural helper cell,” Immunology, vol. 132, no. 4, pp. 475–481, 2011.
[100]
X. Wen, D. Zhang, Y. Kikuchi et al., “Transgene-mediated hyper-expression of IL-5 inhibits autoimmune disease but increases the risk of B cell chronic lymphocytic leukemia in a model of murine lupus,” European Journal of Immunology, vol. 34, no. 10, pp. 2740–2749, 2004.
[101]
N. V. Valeyev, C. Hundhausen, Y. Umezawa et al., “A systems model for immune cell interactions unravels the mechanism of inflammation in human skin,” PLoS Computational Biology, vol. 6, no. 12, Article ID e1001024, 2010.
[102]
E. R. Capper, J. K. Maskill, C. Gordon, and A. I. F. Blakemore, “Interleukin (IL)-10, IL-1ra and IL-12 profiles in active and quiescent systemic lupus erythematosus: could longitudinal studies reveal patient subgroups of differing pathology?” Clinical and Experimental Immunology, vol. 138, no. 2, pp. 348–356, 2004.
[103]
B. Rhodes, J. Meek, J. C. Whittaker, and T. J. Vyse, “Quantification of the genetic component of basal C-reactive protein expression in SLE nuclear families,” Annals of Human Genetics, vol. 72, no. 5, pp. 611–620, 2008.
[104]
E. Meinl, D. Lengenfelder, N. Blank, R. Pirzer, L. Barata, and C. Hivroz, “Differential requirement of ZAP-70 for CD2-mediated activation pathways of mature T cells,” Journal of Immunology, vol. 165, no. 7, pp. 3578–3583, 2000.
[105]
D. Foell, H. Wittkowski, T. Vogl, and J. Roth, “S100 proteins expressed in phagocytes: a novel group of damage-associated molecular pattern molecules,” Journal of Leukocyte Biology, vol. 81, no. 1, pp. 28–37, 2007.
[106]
C. F. Urban, D. Ermert, M. Schmid et al., “Neutrophil extracellular traps contain calprotectin, a cytosolic protein complex involved in host defense against Candida albicans,” PLoS Pathogens, vol. 5, no. 10, Article ID e1000639, 2009.
