Human leukocyte antigen-G expression in differentiated human airway epithelial cells: lack of modulation by Th2-associated cytokines

Respiratory Research

Bertha A Marroquin¹  Timothy Floreth¹  Bharathi Laxman¹  Randi Stern¹  Dagan A Loisel²  Steven R White¹ 

[1] From the Departments of Medicine and Human Genetics, Chicago, IL 60637, USA;Human Genetics, University of Chicago, Chicago, IL 60637, USA

关键词: Asthma;    IL-10;    IL-5;    IL-4;    IL-13;    Airway epithelium;    HLA-G;   

Others  :  796560
DOI  :  10.1186/1465-9921-14-4

 received in 2012-10-03, accepted in 2013-01-11,  发布年份 2013

【 摘 要 】

Background

Human leukocyte antigen (HLA)-G is a nonclassical class I antigen with immunomodulatory roles including up-regulation of suppressor T regulatory lymphocytes. HLA-G was recently identified as an asthma susceptibility gene, and expression of a soluble isoform, HLA-G5, has been demonstrated in human airway epithelium. Increased presence of HLA-G5 has been demonstrated in bronchoalveolar lavage fluid recovered from patients with mild asthma; this suggests a role for this isoform in modulating airway inflammation though the mechanisms by which this occurs is unclear. Airway inflammation associated with Th2 cytokines such as IL-4 and IL-13 is a principal feature of asthma, but whether these cytokines elicit expression of HLA-G is not known.

Methods

We examined gene and protein expression of both soluble (G5) and membrane-bound (G1) HLA-G isoforms in primary differentiated human airway epithelial cells collected from normal lungs and grown in air-liquid interface culture. Cells were treated with up to 10 ng/ml of either IL-4, IL-5, or IL-13, or 100 ng/ml of the immunomodulatory cytokine IL-10, or 10,000 U/ml of the Th1-associated cytokine interferon-beta, for 24 hr, after which RNA was isolated for evaluation by quantitative PCR and protein was collected for Western blot analysis.

Results

HLA-G5 but not G1 was present in dAEC as demonstrated by quantitative PCR, western blot and confocal microscopy. Neither G5 nor G1 expression was increased by the Th2-associated cytokines IL-4, IL-5 or IL-13 over 24 hr, nor after treatment with IL-10, but was increased 4.5 ± 1.4 fold after treatment with 10,000 U/ml interferon-beta.

Conclusions

These data demonstrate the constitutive expression of a T lymphocyte regulatory molecule in differentiated human airway epithelial cells that is not modulated by Th2-associated cytokines.

【 授权许可】

   
2013 White et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

Figure 4.

Figure 5.

Figure 6.

【 参考文献 】

• [1](EPR3) EPR: Guidelines for the Diagnosis and Management of Asthma. National Heart Lung and Blood Institute: Bethesda; 2007.
• [2]Asher MI, Montefort S, Bjorksten B, Lai CK, Strachan DP, Weiland SK, Williams H: Worldwide time trends in the prevalence of symptoms of asthma, allergic rhinoconjunctivitis, and eczema in childhood: ISAAC Phases One and Three repeat multicountry cross-sectional surveys. Lancet 2006, 368:733-743.
• [3]Bradley BL, Azzawi M, Jacobson M, Assoufi B, Collins JV, Irani AM, Schwartz LB, Durham SR, Jeffery PK, Kay AB: Eosinophils, T-lymphocytes, mast cells, neutrophils, and macrophages in bronchial biopsy specimens from atopic subjects with asthma: comparison with biopsy specimens from atopic subjects without asthma and normal control subjects and relationship to bronchial hyperresponsiveness. J Allergy Clin Immunol 1991, 88:661-674.
• [4]Carroll N, Cooke C, James A: The distribution of eosinophils and lymphocytes in the large and small airways of asthmatics. Eur Respir J 1997, 10:292-300.
• [5]Robinson DS, Hamid Q, Ying S, Tsicopoulos A, Barkans J, Bentley AM, Corrigan C, Durham SR, Kay AB: Predominant TH2-like bronchoalveolar T-lymphocyte population in atopic asthma. N Engl J Med 1992, 326:298-304.
• [6]Huang SK, Xiao HQ, Kleine-Tebbe J, Paciotti G, Marsh DG, Lichtenstein LM, Liu MC: IL-13 expression at the sites of allergen challenge in patients with asthma. J Immunol 1995, 155:2688-2694.
• [7]Chen W, Hunninghake GW: Effects of ragweed and Th-2 cytokines on the secretion of IL-8 in human airway epithelial cells. Exp Lung Res 2000, 26:229-239.
• [8]Kobayashi I, Yamamoto S, Nishi N, Tsuji K, Imayoshi M, Inada S, Ichiamaru T, Hamasaki Y: Regulatory mechanisms of Th2 cytokine-induced eotaxin-3 production in bronchial epithelial cells: possible role of interleukin 4 receptor and nuclear factor-kappaB. Ann Allergy Asthma Immunol 2004, 93:390-397.
• [9]Nakamura Y, Azuma M, Okano Y, Sano T, Takahashi T, Ohmoto Y, Sone S: Upregulatory effects of interleukin-4 and interleukin-13 but not interleukin-10 on granulocyte/macrophage colony-stimulating factor production by human bronchial epithelial cells. Am J Respir Cell Mol Biol 1996, 15:680-687.
• [10]van Wetering S, Zuyderduyn S, Ninaber DK, van Sterkenburg MA, Rabe KF, Hiemstra PS: Epithelial differentiation is a determinant in the production of eotaxin-2 and −3 by bronchial epithelial cells in response to IL-4 and IL-13. Mol Immunol 2007, 44:803-811.
• [11]Ying S, Robinson DS, Meng Q, Rottman J, Kennedy R, Ringler DJ, Mackay CR, Daugherty BL, Springer MS, Durham SR, et al.: Enhanced expression of eotaxin and CCR3 mRNA and protein in atopic asthma. Association with airway hyperresponsiveness and predominant co-localization of eotaxin mRNA to bronchial epithelial and endothelial cells. Eur J Immunol 1997, 27:3507-3516.
• [12]Rankin JA, Picarella DE, Geba GP, Temann UA, Prasad B, DiCosmo B, Tarallo A, Stripp B, Whitsett J, Flavell RA: Phenotypic and physiologic characterization of transgenic mice expressing interleukin 4 in the lung: lymphocytic and eosinophilic inflammation without airway hyperreactivity. Proc Natl Acad Sci U S A 1996, 93:7821-7825.
• [13]Vignola AM, Chanez P, Chiappara G, Merendino A, Pace E, Rizzo A, la Rocca AM, Bellia V, Bonsignore G, Bousquet J: Transforming growth factor-beta expression in mucosal biopsies in asthma and chronic bronchitis. Am J Respir Crit Care Med 1997, 156:591-599.
• [14]Zhu Z, Homer RJ, Wang Z, Chen Q, Geba GP, Wang J, Zhang Y, Elias JA: Pulmonary expression of interleukin-13 causes inflammation, mucus hypersecretion, subepithelial fibrosis, physiologic abnormalities, and eotaxin production. J Clin Invest 1999, 103:779-788.
• [15]Geraghty DE, Koller BH, Orr HT: A human major histocompatibility complex class I gene that encodes a protein with a shortened cytoplasmic segment. Proc Natl Acad Sci U S A 1987, 84:9145-9149.
• [16]Fujii T, Ishitani A, Geraghty DE: A soluble form of the HLA-G antigen is encoded by a messenger ribonucleic acid containing intron 4. J Immunol 1994, 153:5516-5524.
• [17]Ishitani A, Geraghty DE: Alternative splicing of HLA-G transcripts yields proteins with primary structures resembling both class I and class II antigens. Proc Natl Acad Sci U S A 1992, 89:3947-3951.
• [18]Hunt JS, Petroff MG, McIntire RH, Ober C: HLA-G and immune tolerance in pregnancy. FASEB J 2005, 19:681-693.
• [19]Rouas-Freiss N, Naji A, Durrbach A, Carosella ED: Tolerogenic functions of human leukocyte antigen G: from pregnancy to organ and cell transplantation. Transplantation 2007, 84:S21-25.
• [20]Hviid TV: HLA-G in human reproduction: aspects of genetics, function and pregnancy complications. Hum Reprod Update 2006, 12:209-232.
• [21]Carosella ED, Moreau P, Lemaoult J, Rouas-Freiss N: HLA-G: from biology to clinical benefits. Trends Immunol 2008, 29:125-132.
• [22]Nicolae D, Cox NJ, Lester LA, Schneider D, Tan Z, Billstrand C, Kuldanek S, Donfack J, Kogut P, Patel NM, et al.: Fine mapping and positional candidate studies identify HLA-G as an asthma susceptibility gene on chromosome 6p21. Am J Hum Genet 2005, 76:349-357.
• [23]Tan Z, Randall G, Fan J, Camoretti-Mercado B, Brockman-Schneider R, Pan L, Solway J, Gern JE, Lemanske RF, Nicolae D, Ober C: Allele-specific targeting of microRNAs to HLA-G and risk of asthma. Am J Hum Genet 2007, 81:829-834.
• [24]Tahan F, Patiroglu T: Plasma soluble human leukocyte antigen G levels in asthmatic children. Int Arch Allergy Immunol 2006, 141:213-216.
• [25]Zheng XQ, Li CC, Xu DP, Lin A, Bao WG, Yang GS, Yan WH: Analysis of the plasma soluble human leukocyte antigen-G and interleukin-10 levels in childhood atopic asthma. Hum Immunol 2010, 71:982-987.
• [26]White SR, Loisel DA, McConville JF, Stern R, Tu Y, Marroquin BA, Noth I, Ober C: Levels of soluble human leukocyte antigen-G are increased in asthmatic airways. Eur Respir J 2010, 35:925-927.
• [27]Colonna M, Navarro F, Bellon T, Llano M, Garcia P, Samaridis J, Angman L, Cella M, Lopez-Botet M: A common inhibitory receptor for major histocompatibility complex class I molecules on human lymphoid and myelomonocytic cells. J Exp Med 1997, 186:1809-1818.
• [28]Colonna M, Samaridis J, Cella M, Angman L, Allen RL, O'Callaghan CA, Dunbar R, Ogg GS, Cerundolo V, Rolink A: Human myelomonocytic cells express an inhibitory receptor for classical and nonclassical MHC class I molecules. J Immunol 1998, 160:3096-3100.
• [29]Shiroishi M, Tsumoto K, Amano K, Shirakihara Y, Colonna M, Braud VM, Allan DS, Makadzange A, Rowland-Jones S, Willcox B, et al.: Human inhibitory receptors Ig-like transcript 2 (ILT2) and ILT4 compete with CD8 for MHC class I binding and bind preferentially to HLA-G. Proc Natl Acad Sci U S A 2003, 100:8856-8861.
• [30]Riteau B, Rouas-Freiss N, Menier C, Paul P, Dausset J, Carosella ED: HLA-G2, -G3, and -G4 isoforms expressed as nonmature cell surface glycoproteins inhibit NK and antigen-specific CTL cytolysis. J Immunol 2001, 166:5018-5026.
• [31]Lila N, Rouas-Freiss N, Dausset J, Carpentier A, Carosella ED: Soluble HLA-G protein secreted by allo-specific CD4+ T cells suppresses the allo-proliferative response: a CD4+ T cell regulatory mechanism. Proc Natl Acad Sci U S A 2001, 98:12150-12155.
• [32]Contini P, Ghio M, Poggi A, Filaci G, Indiveri F, Ferrone S, Puppo F: Soluble HLA-A,-B,-C and -G molecules induce apoptosis in T and NK CD8+ cells and inhibit cytotoxic T cell activity through CD8 ligation. Eur J Immunol 2003, 33:125-134.
• [33]Naji A, Le Rond S, Durrbach A, Krawice-Radanne I, Creput C, Daouya M, Caumartin J, LeMaoult J, Carosella ED, Rouas-Freiss N: CD3+CD4low and CD3+CD8low are induced by HLA-G: novel human peripheral blood suppressor T-cell subsets involved in transplant acceptance. Blood 2007, 110:3936-3948.
• [34]Kanai T, Fujii T, Unno N, Yamashita T, Hyodo H, Miki A, Hamai Y, Kozuma S, Taketani Y: Human leukocyte antigen-G-expressing cells differently modulate the release of cytokines from mononuclear cells present in the decidua versus peripheral blood. Am J Reprod Immunol 2001, 45:94-99.
• [35]Tomita K, Lim S, Hanazawa T, Usmani O, Stirling R, Chung KF, Barnes PJ, Adcock IM: Attenuated production of intracellular IL-10 and IL-12 in monocytes from patients with severe asthma. Clin Immunol 2002, 102:258-266.
• [36]Rizzo R, Mapp CE, Melchiorri L, Maestrelli P, Visentin A, Ferretti S, Bononi I, Miotto D, Baricordi OR: Defective production of soluble HLA-G molecules by peripheral blood monocytes in patients with asthma. J Allergy Clin Immunol 2005, 115:508-513.
• [37]Kim KW, Lee KE, Hong JY, Kim MN, Heo WI, Sohn MH, Kim KE: Involvement of IL-10 gene promoter polymorphisms in the susceptibility for childhood asthma. Lung 2011, 189:417-423.
• [38]Karjalainen J, Hulkkonen J, Nieminen MM, Huhtala H, Aromaa A, Klaukka T, Hurme M: Interleukin-10 gene promoter region polymorphism is associated with eosinophil count and circulating immunoglobulin E in adult asthma. Clin Exp Allergy 2003, 33:78-83.
• [39]White SR, Fischer BM, Marroquin BA, Stern R: Interleukin-1{beta} mediates human airway epithelial cell migration via NF-{kappa}B. Am J Physiol Lung Cell Mol Physiol 2008, 295:L1018-1027.
• [40]White SR, Martin LD, Abe MK, Marroquin BA, Stern R, Fu X: Insulin receptor substrate-1/2 mediates IL-4-induced migration of human airway epithelial cells. Am J Physiol Lung Cell Mol Physiol 2009, 297:L164-173.
• [41]Gomperts BN, Belperio JA, Rao PN, Randell SH, Fishbein MC, Burdick MD, Strieter RM: Circulating progenitor epithelial cells traffic via CXCR4/CXCL12 in response to airway injury. J Immunol 2006, 176:1916-1927.
• [42]Voynow JA, Fischer BM, Roberts BC, Proia AD: Basal-like cells constitute the proliferating cell population in cystic fibrosis airways. Am J Respir Crit Care Med 2005, 172:1013-1018.
• [43]Bernacki SH, Nelson AL, Abdullah L, Sheehan JK, Harris A, Davis CW, Randell SH: Mucin gene expression during differentiation of human airway epithelia in vitro. Muc4 and muc5b are strongly induced. Am J Respir Cell Mol Biol 1999, 20:595-604.
• [44]Lopez-Ferrer A, Curull V, Barranco C, Garrido M, Lloreta J, Real FX, de Bolos C: Mucins as differentiation markers in bronchial epithelium. Squamous cell carcinoma and adenocarcinoma display similar expression patterns. Am J Respir Cell Mol Biol 2001, 24:22-29.
• [45]Krunkosky TM, Jordan JL, Chambers E, Krause DC: Mycoplasma pneumoniae host-pathogen studies in an air-liquid culture of differentiated human airway epithelial cells. Microb Pathog 2007, 42:98-103.
• [46]White SR, Tse R, Marroquin BA: Stress-activated protein kinases mediate cell migration in human airway epithelial cells. Am J Respir Cell Mol Biol 2005, 32:301-310.
• [47]Chu W, Yang Y, Geraghty DE, Hunt JS: Interferons enhance HLA-G mRNA and protein in transfected mouse fibroblasts. J Reprod Immunol 1999, 42:1-15.
• [48]Lefebvre S, Berrih-Aknin S, Adrian F, Moreau P, Poea S, Gourand L, Dausset J, Carosella ED, Paul P: A specific interferon (IFN)-stimulated response element of the distal HLA-G promoter binds IFN-regulatory factor 1 and mediates enhancement of this nonclassical class I gene by IFN-beta. J Biol Chem 2001, 276:6133-6139.
• [49]Yamamoto S, Kobayashi I, Tsuji K, Nishi N, Muro E, Miyazaki M, Zaitsu M, Inada S, Ichimaru T, Hamasaki Y: Upregulation of interleukin-4 receptor by interferon-gamma: enhanced interleukin-4-induced eotaxin-3 production in airway epithelium. Am J Respir Cell Mol Biol 2004, 31:456-462.
• [50]Matsukura S, Stellato C, Georas SN, Casolaro V, Plitt JR, Miura K, Kurosawa S, Schindler U, Schleimer RP, Stellato C, et al.: Interleukin-13 upregulates eotaxin expression in airway epithelial cells by a STAT6-dependent mechanism. Am J Respir Cell Mol Biol 2001, 24:755-761.
• [51]Lim S, Caramori G, Tomita K, Jazrawi E, Oates T, Chung KF, Barnes PJ, Adcock IM: Differential expression of IL-10 receptor by epithelial cells and alveolar macrophages. Allergy 2004, 59:505-514.
• [52]Mocellin S, Marincola F, Rossi CR, Nitti D, Lise M: The multifaceted relationship between IL-10 and adaptive immunity: putting together the pieces of a puzzle. Cytokine Growth Factor Rev 2004, 15:61-76.
• [53]Murray PJ: The JAK-STAT signaling pathway: input and output integration. J Immunol 2007, 178:2623-2629.
• [54]Finbloom DS, Winestock KD: IL-10 induces the tyrosine phosphorylation of tyk2 and Jak1 and the differential assembly of STAT1 alpha and STAT3 complexes in human T cells and monocytes. J Immunol 1995, 155:1079-1090.
• [55]Weber-Nordt RM, Riley JK, Greenlund AC, Moore KW, Darnell JE, Schreiber RD: Stat3 recruitment by two distinct ligand-induced, tyrosine-phosphorylated docking sites in the interleukin-10 receptor intracellular domain. J Biol Chem 1996, 271:27954-27961.
• [56]Lai CF, Ripperger J, Morella KK, Jurlander J, Hawley TS, Carson WE, Kordula T, Caligiuri MA, Hawley RG, Fey GH, Baumann H: Receptors for interleukin (IL)-10 and IL-6-type cytokines use similar signaling mechanisms for inducing transcription through IL-6 response elements. J Biol Chem 1996, 271:13968-13975.
• [57]Wehinger J, Gouilleux F, Groner B, Finke J, Mertelsmann R, Weber-Nordt RM: IL-10 induces DNA binding activity of three STAT proteins (Stat1, Stat3, and Stat5) and their distinct combinatorial assembly in the promoters of selected genes. FEBS Lett 1996, 394:365-370.
• [58]Carosella ED, HoWangYin KY, Favier B, LeMaoult J: HLA-G-dependent suppressor cells: Diverse by nature, function, and significance. Hum Immunol 2008, 69:700-707.
• [59]Lee JH, Yu HH, Wang LC, Yang YH, Lin YT, Chiang BL: The levels of CD4+CD25+ regulatory T cells in paediatric patients with allergic rhinitis and bronchial asthma. Clin Exp Immunol 2007, 148:53-63.
• [60]Fujisawa T, Kato Y, Atsuta J, Terada A, Iguchi K, Kamiya H, Yamada H, Nakajima T, Miyamasu M, Hirai K: Chemokine production by the BEAS-2B human bronchial epithelial cells: differential regulation of eotaxin, IL-8, and RANTES by TH2- and TH1-derived cytokines. J Allergy Clin Immunol 2000, 105:126-133.
• [61]Lordan JL, Bucchieri F, Richter A, Konstantinidis A, Holloway JW, Thornber M, Puddicombe SM, Buchanan D, Wilson SJ, Djukanovic R, et al.: Cooperative effects of Th2 cytokines and allergen on normal and asthmatic bronchial epithelial cells. J Immunol 2002, 169:407-414.
• [62]Propst SM, Denson R, Rothstein E, Estell K, Schwiebert LM: Proinflammatory and Th2-derived cytokines modulate CD40-mediated expression of inflammatory mediators in airway epithelia: implications for the role of epithelial CD40 in airway inflammation. J Immunol 2000, 165:2214-2221.
• [63]Atherton HC, Jones G, Danahay H: IL-13-induced changes in the goblet cell density of human bronchial epithelial cell cultures: MAP kinase and phosphatidylinositol 3-kinase regulation. Am J Physiol Lung Cell Mol Physiol 2003, 285:L730-739.
• [64]McIntire RH, Morales PJ, Petroff MG, Colonna M, Hunt JS: Recombinant HLA-G5 and -G6 drive U937 myelomonocytic cell production of TGF-beta1. J Leukoc Biol 2004, 76:1220-1228.