IL-12 p40 homodimer-dependent macrophage chemotaxis and respiratory viral inflammation are mediated through IL-12 receptor β1

被引:65
作者
Russell, TD
Yan, QY
Fan, GS
Khalifah, AP
Bishop, DK
Brody, SL
Walter, MJ
机构
[1] Washington Univ, Sch Med, Dept Med, Div Pulm & Crit Care Med, St Louis, MO 63110 USA
[2] Univ Michigan, Sch Med, Dept Surg, Ann Arbor, MI 48109 USA
关键词
D O I
10.4049/jimmunol.171.12.6866
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
Leukocyte recruitment to the airway lumen is a central feature of inflammatory conditions such as asthma and respiratory viral infection. Characterization of mediators that regulate leukocyte recruitment in these conditions revealed increased IL-12 p40 homodimer (p80) levels were associated with enhanced airway macrophage accumulation. To examine this association, we used in vivo and in vitro assays to demonstrate p80, but not IL-12 or p40, provided a macrophage chemoattractant signal. Macrophages from genetically deficient mice indicated p80-dependent chemotaxis was independent of IL-12 and required IL-12Rbeta1 (Rbeta1) expression. Furthermore, analysis of murine cell lines and primary culture macrophages revealed Rbeta1 expression, with an intact cytoplasmic tail, was necessary and sufficient to mediate p80-dependent chemotaxis. To examine the role for Rbeta1 in mediating macrophage accumulation in vivo, we contrasted Sendai virus-driven airway inflammation in wild-type and Rbeta1-deficient mice. Despite similar viral burden and production of the macrophage chemoattractant p80, the Rbeta1-deficient mice displayed a selective decrease in airway macrophage accumulation and resistance to viral-dependent mortality. Thus, Rbeta1 mediates p80-dependent macrophage chemotaxis and inhibition of the p80-Rbeta1 interaction may provide a novel anti-inflammatory strategy to manipulate the inflammation associated with asthma and respiratory viral infection.
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收藏
页码:6866 / 6874
页数:9
相关论文
共 65 条
[1]   Tumor necrosis factor-α activation of nuclear transcription factor-κB in marrow macrophages is mediated by c-Src tyrosine phosphorylatiola of IκBα [J].
Abu-Amer, Y ;
Ross, FP ;
McHugh, KP ;
Livolsi, A ;
Peyron, JF ;
Teitelbaum, SL .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1998, 273 (45) :29417-29423
[2]  
AKSAMIT RR, 1981, J IMMUNOL, V126, P2194
[3]   Mycobacterium fortuitum-chelonae complex infection in a child with complete interleukin-12 receptor beta 1 deficiency [J].
Aksu, G ;
Tirpan, C ;
Cavusoglu, C ;
Soydan, S ;
Altare, F ;
Casanova, JL ;
Kutukculer, N .
PEDIATRIC INFECTIOUS DISEASE JOURNAL, 2001, 20 (05) :551-553
[4]   Impairment of mycobacterial immunity in human interleukin-12 receptor deficiency [J].
Altare, F ;
Durandy, A ;
Lammas, D ;
Emile, JF ;
Lamhamedi, S ;
Le Deist, F ;
Drysdale, P ;
Jouanguy, E ;
Döffinger, R ;
Bernaudin, F ;
Jeppsson, O ;
Gollob, JA ;
Meinl, E ;
Segal, AW ;
Fischer, A ;
Kumararatne, D ;
Casanova, JL .
SCIENCE, 1998, 280 (5368) :1432-1435
[5]  
BANDA MJ, 1988, J BIOL CHEM, V263, P4481
[6]  
CARPENTER CL, 1993, J BIOL CHEM, V268, P9478
[7]  
Chen L, 1997, J IMMUNOL, V159, P351
[8]  
CHUA AO, 1995, J IMMUNOL, V155, P4286
[9]   Signaling pathways controlling cell polarity and chemotaxis [J].
Chung, CY ;
Funamoto, S ;
Firtel, RA .
TRENDS IN BIOCHEMICAL SCIENCES, 2001, 26 (09) :557-566
[10]   How is actin polymerization nucleated in vivo? [J].
Condeelis, J .
TRENDS IN CELL BIOLOGY, 2001, 11 (07) :288-293