Inducible expression of type 2 IL-1 receptors by cultured human keratinocytes. Implications for IL-1-mediated processes in epidermis.
Two species of cell surface receptor for IL-1 (IL-1R) have been characterized. Only one of these, the type 1 IL-1R, transduces a signal after ligand binding. Whereas mRNA for the nonsignal transducing type 2 IL-1R seems to have a broad tissue distribution, functional type 2 IL-1R has been carefully studied only in leukocytes and related cell lines. Because normal human keratinocytes, which are IL-1 alpha-producing epithelial cells, inducibly express large numbers of IL-1R, we have studied their putative type 1 and type 2 IL-1R at the level of RNA, protein, and biologic function. At the level of function, gene expression of the IL-1-inducible cytokine granulocyte-macrophage-CSF by keratinocytes was mediated entirely by low numbers of type 1 IL-1R, although type 2 IL-1R were more numerous on both resting and activated keratinocytes. Type I IL-1R mRNA was detected only at very low levels, whereas a marked induction of type 2 IL-1R mRNA was readily observed in activated keratinocytes. A sensitive and specific ELISA demonstrated shed type 2 IL-1R in the conditioned medium of IFN-gamma or PMA-activated keratinocytes. Keratinocyte type 2 IL-1R bound IL-1 alpha with higher affinity (Kd approximately 3 x 10(-9) M) than type 2 IL-1R on leukocytes; however, the intracellular epithelial form of the IL-1R antagonist was bound 100-fold less avidly. These findings demonstrate that a normal nontransformed epithelial cell may express large numbers of the nonsignal transducing type 2 IL-1R that binds IL-1 with high affinity and can be shed into the pericellular environment. This receptor may function as an IL-1 antagonist in autocrine, juxtacrine, and paracrine cutaneous pathways.
Groves
R W
RW
Harvard Skin Disease Research Center, Division of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Giri
J
J
Sims
J
J
Dower
S K
SK
Kupper
T S
TS
D001483:Base Sequence; D002478:Cells, Cultured; D017931:DNA Primers / Q000737:chemistry; D015870:Gene Expression; D006801:Humans; D066298:In Vitro Techniques; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1 / Q000378:metabolism*; D015603:Keratinocytes / Q000502:physiology*; D008297:Male; D008969:Molecular Sequence Data; D008970:Molecular Weight; D012333:RNA, Messenger / Q000235:genetics; D017472:Receptors, Interleukin-1 / Q000145:classification / Q000235:genetics / Q000378:metabolism*; D012795:Sialoglycoproteins / Q000378:metabolism
D017931:DNA Primers; C507763:IL1RN protein, human; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; D012333:RNA, Messenger; D017472:Receptors, Interleukin-1; D012795:Sialoglycoproteins