Cytokine dysregulation in activated cystic fibrosis (CF) peripheral lymphocytes

被引:93
作者
Moss, RB [1 ]
Hsu, YP [1 ]
Olds, L [1 ]
机构
[1] Stanford Univ, Sch Med, Dept Paediat, Palo Alto, CA 94304 USA
关键词
cystic fibrosis; inflammation; cytokines; interferon; interleukin;
D O I
10.1046/j.1365-2249.2000.01232.x
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
Recent studies demonstrate in vivo and in vitro cytokine dysregulation in CF epithelial cells. To see if these abnormalities may be generalized to other cells expressing cystic fibrosis transmembrane conductance regulator (CFTR) but not directly exposed to local inflammation, we studied mRNA transcription, intracellular protein production and extracellular secretion of IL-2, IL-4, IL-5, IL-10 and interferon-gamma (IFN-gamma) from freshly isolated blood mononuclear and CD4(+) T cells from CF patients and controls. Cells were activated by phorbol myristate acetate (PMA) and anti-CD3, PMA-ionomycin, or lipopolysaccharide (LPS) and assessed for cytokine mRNA transcription by semiquantitative reverse transcriptase-polymerase chain reaction, intracellular protein production by flow cytometry, and secretion by supernatant ELISA. Cytokine expression was highly stimulus-dependent. CF cells showed higher IL-10 transcription than control cells after maximal activation by LPS (P = 0.01); despite this, cytokine production and secretion were equivalent to controls. CF cells showed lower cellular IL-IO production after PMA-anti-CD3 activation (P = 0.002). CF cells secreted less lFN-gamma than control cells after maximal activation by PMA-anti-CD3 (1836 +/- 273 pg/ml versus 9635 +/- 3437 pg/ml, P = 0.04). IL-2, IL-4 and IL-5 regulation was similar to controls. We conclude that CF mononuclear cells show selective cytokine dysregulation after maximal activation, namely reduced lFN-gamma secretion and increased IL-IO mRNA without increased production or secretion. These findings extend defects described in respiratory epithelial cells to circulating immunoregulatory cells, suggesting a link between CF genotype and cytokine dysregulation.
引用
收藏
页码:518 / 525
页数:8
相关论文
共 45 条
  • [1] ABRAMS JS, 1995, CURRENT PROTOCOLS S, V13
  • [2] Cationic lipid-mediated CFTR gene transfer to the lungs and nose of patients with cystic fibrosis:: a double-blind placebo-controlled trial
    Alton, EWFW
    Stern, M
    Farley, R
    Jaffe, A
    Chadwick, SL
    Phillips, J
    Davies, J
    Smith, SN
    Browning, J
    Davies, MG
    Hodson, ME
    Durham, SR
    Li, D
    Jeffery, PK
    Scallan, M
    Balfour, R
    Eastman, SJ
    Cheng, SH
    Smith, AE
    Meeker, D
    Geddes, DM
    [J]. LANCET, 1999, 353 (9157) : 947 - 954
  • [3] Lower airway inflammation in infants and young children with cystic fibrosis
    Armstrong, DS
    Grimwood, K
    Carlin, JB
    Carzino, R
    Gutierrez, JP
    Hull, J
    Olinsky, A
    Phelan, EM
    Robertson, CF
    Phelan, PD
    [J]. AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, 1997, 156 (04) : 1197 - 1204
  • [4] THE RELATIONSHIP BETWEEN INFECTION AND INFLAMMATION IN THE EARLY STAGES OF LUNG-DISEASE FROM CYSTIC-FIBROSIS
    BALOUGH, K
    MCCUBBIN, M
    WEINBERGER, M
    SMITS, W
    AHRENS, R
    FICK, R
    [J]. PEDIATRIC PULMONOLOGY, 1995, 20 (02) : 63 - 70
  • [5] RELEASE OF INTERLEUKIN-8, INTERLEUKIN-6, AND COLONY-STIMULATING FACTORS BY UPPER AIRWAY EPITHELIAL-CELLS - IMPLICATIONS FOR CYSTIC-FIBROSIS
    BEDARD, M
    MCCLURE, CD
    SCHILLER, NL
    FRANCOEUR, C
    CANTIN, A
    DENIS, M
    [J]. AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY, 1993, 9 (04) : 455 - 462
  • [6] Interleukin-8 production by cystic fibrosis nasal epithelial cells after tumor necrosis factor-α and respiratory syncytial virus stimulation
    Black, HR
    Yankaskas, JR
    Johnson, LG
    Noah, TL
    [J]. AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY, 1998, 19 (02) : 210 - 215
  • [7] THE EFFECTS OF NEBULIZED RECOMBINANT INTERFERON-GAMMA IN ASTHMATIC AIRWAYS
    BOGUNIEWICZ, M
    MARTIN, RJ
    MARTIN, D
    GIBSON, U
    CELNIKER, A
    WILLIAMS, M
    LEUNG, DYM
    [J]. JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY, 1995, 95 (01) : 133 - 135
  • [8] Altered respiratory epithelial cell cytokine production in cystic fibrosis
    Bonfield, TL
    Konstan, MW
    Berger, M
    [J]. JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY, 1999, 104 (01) : 72 - 78
  • [9] INFLAMMATORY CYTOKINES IN CYSTIC-FIBROSIS LUNGS
    BONFIELD, TL
    PANUSKA, JR
    KONSTAN, MW
    HILLIARD, KA
    HILLIARD, JB
    GHNAIM, H
    BERGER, M
    [J]. AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, 1995, 152 (06) : 2111 - 2118
  • [10] NORMAL BRONCHIAL EPITHELIAL-CELLS CONSTITUTIVELY PRODUCE THE ANTIINFLAMMATORY CYTOKINE INTERLEUKIN-10, WHICH IS DOWN-REGULATED IN CYSTIC-FIBROSIS
    BONFIELD, TL
    KONSTAN, MW
    BURFEIND, P
    PANUSKA, JR
    HILLIARD, JB
    BERGER, M
    [J]. AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY, 1995, 13 (03) : 257 - 261