Human IL-32 expression protects mice against a hypervirulent strain of Mycobacterium tuberculosis

被引:48
作者
Bai, Xiyuan [1 ,3 ]
Shang, Shaobin [2 ]
Henao-Tamayo, Marcela [2 ]
Basaraba, Randall J. [2 ]
Ovrutsky, Alida R. [1 ,3 ,8 ]
Matsuda, Jennifer L. [3 ]
Takeda, Katsuyuki [4 ]
Chan, Mallory M. [3 ]
Dakhama, Azzeddine [4 ]
Kinney, William H. [3 ]
Trostel, Jessica [3 ]
Bai, An [3 ]
Honda, Jennifer R. [3 ,8 ]
Achcar, Rosane [5 ]
Hartney, John [3 ]
Joosten, Leo A. B. [6 ]
Kim, Soo-Hyun [7 ]
Orme, Ian [2 ]
Dinarello, Charles A. [6 ,9 ]
Ordway, Diane J. [2 ]
Chan, Edward D. [1 ,3 ,8 ]
机构
[1] Denver Vet Affairs Med Ctr, Denver, CO 80206 USA
[2] Colorado State Univ, Dept Microbiol Immunol & Pathol, Mycobacteria Res Labs, Ft Collins, CO 80523 USA
[3] Natl Jewish Hlth, Dept Med, Denver, CO 80206 USA
[4] Natl Jewish Hlth, Dept Pediat, Denver, CO 80206 USA
[5] Natl Jewish Hlth, Dept Pathol, Denver, CO 80206 USA
[6] Radboud Univ Nijmegen, Med Ctr, Dept Internal Med, Nijmegen, Netherlands
[7] Konkuk Univ, Dept Biomed Sci & Technol, Seoul, South Korea
[8] Univ Colorado, Div Pulm Sci & Crit Care Med, Aurora, CO 80045 USA
[9] Univ Colorado, Div Infect Dis, Aurora, CO 80045 USA
基金
美国国家卫生研究院; 新加坡国家研究基金会;
关键词
cytokine; transgenic mouse; tuberculosis; host immunity; interleukin-32; PROINFLAMMATORY CYTOKINE; INTERLEUKIN-32; INFLAMMATION; IL-32-GAMMA; CELLS;
D O I
10.1073/pnas.1424302112
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Silencing of interleukin-32 (IL-32) in a differentiated human promonocytic cell line impairs killing of Mycobacterium tuberculosis (MTB) but the role of IL-32 in vivo against MTB remains unknown. To study the effects of IL-32 in vivo, a transgenic mouse was generated in which the human IL-32 gamma gene is expressed using the surfactant protein C promoter (SPC-IL-32 gamma Tg). Wild-type and SPC-IL-32 gamma Tg mice were infected with a low-dose aerosol of a hypervirulent strain of MTB (W-Beijing HN878). At 30 and 60 d after infection, the transgenic mice had 66% and 85% fewer MTB in the lungs and 49% and 68% fewer MTB in the spleens, respectively; the transgenic mice also exhibited greater survival. Increased numbers of host-protective innate and adaptive immune cells were present in SPC-IL-32 gamma Tg mice, including tumor necrosis factor-alpha (TNF alpha) positive lung macrophages and dendritic cells, and IFN-gamma (IFN gamma) and TNF alpha positive CD4(+) and CD8(+) T cells in the lungs and mediastinal lymph nodes. Alveolar macrophages from transgenic mice infected with MTB ex vivo had reduced bacterial burden and increased colocalization of green fluorescent protein-labeled MTB with lysosomes. Furthermore, mouse macrophages made to express IL-32. but not the splice variant IL-32 beta were better able to limit MTB growth than macrophages capable of producing both. The lungs of patients with tuberculosis showed increased IL-32 expression, particularly in macrophages of granulomas and airway epithelial cells but also B cells and T cells. We conclude that IL-32 gamma enhances host immunity to MTB.
引用
收藏
页码:5111 / 5116
页数:6
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