Two novel IL-1 family members, IL-1δ and IL-1ε, function as an antagonist and agonist of NF-κB activation through the orphan IL-1 receptor-related protein 2

被引:218
作者
Debets, R [1 ]
Timans, JC [1 ]
Homey, B [1 ]
Zurawski, S [1 ]
Sana, TR [1 ]
Lo, S [1 ]
Wagner, J [1 ]
Edwards, G [1 ]
Clifford, T [1 ]
Menon, S [1 ]
Bazan, JF [1 ]
Kastelein, RA [1 ]
机构
[1] DNAX Res Inst Mol & Cellular Biol Inc, Palo Alto, CA 94304 USA
关键词
D O I
10.4049/jimmunol.167.3.1440
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
IL-1 is of utmost importance in the host response to immunological challenges. We identified and functionally characterized two novel IL-1 ligands termed IL-1 delta and IL-1 epsilon. Northern blot analyses show that these IL-1s are highly abundant in embryonic tissue and tissues containing epithelial cells (i.e., skin, lung, and stomach). In extension, quantitative real-time PCR revealed that of human skin-derived cells, only keratinocytes but not fibroblasts, endothelial cells, or melanocytes express IL-1 delta and epsilon. Levels of keratinocyte IL-1 delta are similar to 10-fold higher than those of IL-1 epsilon. In vitro stimulation of keratinocytes with IL-1 beta /TNF-alpha significantly up-regulates the expression of IL-1 epsilon mRNA, and to a lesser extent of IL-1 delta mRNA. In NF-kappaB-luciferase reporter assays, we demonstrated that IL-1 delta and epsilon proteins do not initiate a functional response via classical IL-1R pairs, which confer responsiveness to IL-1 alpha and beta or IL-1 delta. However, IL-1 epsilon activates NF-kappaB through the orphan IL-1R-related protein 2 (IL-1Rrp2), whereas IL-1 delta, which shows striking homology to IL-1 receptor antagonist, specifically and potently inhibits this IL-1 epsilon response. In lesional psoriasis skin, characterized by chronic cutaneous inflammation, the mRNA expression of both IL-1 ligands as well as IL-1Rrp2 are increased relative to normal healthy skin. In total, IL-1 delta and epsilon and IL-1Rrp2 may constitute an independent signaling system, analogous to IL-1 alpha beta /receptor agonist and IL-1R1, that is present in epithelial barriers of our body and takes part in local inflammatory responses.
引用
收藏
页码:1440 / 1446
页数:7
相关论文
共 54 条
[1]  
Barton JL, 2000, EUR J IMMUNOL, V30, P3299, DOI 10.1002/1521-4141(200011)30:11<3299::AID-IMMU3299>3.0.CO
[2]  
2-S
[3]   A newly defined interleukin-1? [J].
Bazan, JF ;
Timans, JC ;
Kastelein, RA .
NATURE, 1996, 379 (6566) :591-591
[4]   Cloning of a novel receptor subunit, AcPL, required for interleukin-18 signaling [J].
Born, TL ;
Thomassen, E ;
Bird, TA ;
Sims, JE .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1998, 273 (45) :29445-29450
[5]   Identification and gene organization of three novel members of the IL-1 family on human chromosome 2 [J].
Busfield, SJ ;
Comrack, CA ;
Yu, G ;
Chickering, TW ;
Smutko, JS ;
Zhou, H ;
Leiby, KR ;
Holmgren, LM ;
Gearing, DP ;
Pan, Y .
GENOMICS, 2000, 66 (02) :213-216
[6]   A new member of the IL-1 receptor family highly expressed in hippocampus and involved in X-linked mental retardation [J].
Carrié, A ;
Jun, L ;
Bienvenu, T ;
Vinet, MC ;
McDonell, N ;
Couvert, P ;
Zemni, R ;
Cardona, A ;
Van Buggenhout, G ;
Frints, S ;
Hamel, B ;
Moraine, C ;
Ropers, HH ;
Strom, T ;
Howell, GR ;
Whittaker, A ;
Ross, MT ;
Kahn, A ;
Fryns, JP ;
Beldjord, C ;
Marynen, P ;
Chelly, J .
NATURE GENETICS, 1999, 23 (01) :25-31
[7]   THE TYPE-II DECOY RECEPTOR - A NOVEL REGULATORY PATHWAY FOR INTERLEUKIN-1 [J].
COLOTTA, F ;
DOWER, SK ;
SIMS, JE ;
MANTOVANI, A .
IMMUNOLOGY TODAY, 1994, 15 (12) :562-566
[8]  
Cullinan EB, 1998, J IMMUNOL, V161, P5614
[9]   Interleukin-1 receptor cluster:: Gene organization of IL1R2, IL1R1, IL1RL2 (IL-1Rrp2), IL1RL1 (T1/ST2), and IL18R1 (IL-1Rrp) on human chromosome 2q [J].
Dale, M ;
Nicklin, MJH .
GENOMICS, 1999, 57 (01) :177-179
[10]  
Debets R, 1997, J IMMUNOL, V158, P2955