Two novel IL-1 family members, IL-1 delta and IL-1 epsilon, function as an antagonist and agonist of NF-kappa B activation through the orphan IL-1 receptor-related protein 2.
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-1delta and IL-1epsilon. 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-1delta and epsilon. Levels of keratinocyte IL-1delta are approximately 10-fold higher than those of IL-1epsilon. In vitro stimulation of keratinocytes with IL-1beta/TNF-alpha significantly up-regulates the expression of IL-1epsilon mRNA, and to a lesser extent of IL-1delta mRNA. In NF-kappaB-luciferase reporter assays, we demonstrated that IL-1delta and epsilon proteins do not initiate a functional response via classical IL-1R pairs, which confer responsiveness to IL-1alpha and beta or IL-18. However, IL-1epsilon activates NF-kappaB through the orphan IL-1R-related protein 2 (IL-1Rrp2), whereas IL-1delta, which shows striking homology to IL-1 receptor antagonist, specifically and potently inhibits this IL-1epsilon 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-1delta and epsilon and IL-1Rrp2 may constitute an independent signaling system, analogous to IL-1alphabeta/receptor agonist and IL-1R1, that is present in epithelial barriers of our body and takes part in local inflammatory responses.
Debets
R
R
DNAX Research Institute of Molecular and Cellular Biology, 901 California Avenue, Palo Alto, CA 94304, USA.
Timans
J C
JC
Homey
B
B
Zurawski
S
S
Sana
T R
TR
Lo
S
S
Wagner
J
J
Edwards
G
G
Clifford
T
T
Menon
S
S
Bazan
J F
JF
Kastelein
R A
RA
D000595:Amino Acid Sequence; D000818:Animals; D002478:Cells, Cultured; D004622:Embryo, Mammalian; D004847:Epithelial Cells / Q000276:immunology / Q000378:metabolism; D006801:Humans; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1 / Q000819:agonists* / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000502:physiology*; D053727:Interleukin-18 Receptor alpha Subunit; D019169:Jurkat Cells; D008024:Ligands; D051379:Mice; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009928:Organ Specificity / Q000235:genetics / Q000276:immunology; D011506:Proteins / Q000502:physiology*; D011565:Psoriasis / Q000276:immunology / Q000473:pathology; D012333:RNA, Messenger / Q000096:biosynthesis; D017472:Receptors, Interleukin-1 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000502:physiology; D053724:Receptors, Interleukin-18; D016415:Sequence Alignment; D012795:Sialoglycoproteins / Q000502:physiology; D015854:Up-Regulation / Q000276:immunology
C508572:IL18R1 protein, human; C507763:IL1RN protein, human; C508573:Il18r1 protein, mouse; C507764:Il1rn protein, mouse; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; D053727:Interleukin-18 Receptor alpha Subunit; D008024:Ligands; D016328:NF-kappa B; D011506:Proteins; D012333:RNA, Messenger; D017472:Receptors, Interleukin-1; D053724:Receptors, Interleukin-18; D012795:Sialoglycoproteins; C437372:interleukin-1 delta; C437373:interleukin-1 epsilon