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and IL-1
, Function as an Antagonist and Agonist of NF-
B Activation Through the Orphan IL-1 Receptor-Related Protein 21
DNAX Research Institute of Molecular and Cellular Biology, Palo Alto, CA 94304
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
and IL-1
. 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 and . Levels of keratinocyte
IL-1 are 
10-fold higher than those of IL-1. In vitro
stimulation of keratinocytes with IL-1
/TNF-
significantly
up-regulates the expression of IL-1 mRNA, and to a lesser extent of
IL-1 mRNA. In NF-
B-luciferase reporter assays, we demonstrated
that IL-1 and proteins do not initiate a functional response via
classical IL-1R pairs, which confer responsiveness to IL-1 and
or IL-18. However, IL-1 activates NF-B through the orphan
IL-1R-related protein 2 (IL-1Rrp2), whereas IL-1, which shows
striking homology to IL-1 receptor antagonist, specifically and
potently inhibits this IL-1 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 and and IL-1Rrp2 may constitute an
independent signaling system, analogous to IL-1/receptor agonist
and IL-1R1, that is present in epithelial barriers of our body and
takes part in local inflammatory responses.
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