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Cloning and Characterization of Two Toll/Interleukin-1 Receptor-Like
Genes TIL3 and TIL4: Evidence for a Multi-Gene Receptor Family in
Humans
Preet M. Chaudhary,
Camari Ferguson,
Vilaska Nguyen,
Oanh Nguyen,
Hillary F. Massa,
Michael Eby,
Alan Jasmin,
Barbara J. Trask,
Leroy Hood, and
Peter S. Nelson
From the Department of Medicine and Molecular Biotechnology,
University of Washington, Seattle, WA.
Remarkable structural and functional similarities exist between the
Drosophila Toll/Cactus/Dorsal signaling pathway and the mammalian cytokine-mediated interleukin-1 receptor
(IL-1R)/I- B/NF-B activation cascade. In addition to a role
regulating dorsal-ventral polarity in the developing Drosophila
embryo, signaling through Drosophila Toll (dToll) activates the
nonclonal, or innate, immune response in the adult fly. Recent evidence
indicates that a human homologue of the dToll protein participates in
the regulation of both innate and adaptive human immunity through the
activation of NF-B and the expression of the NF-B-controlled
genes IL-1, IL-6, and IL-8, thus affirming the evolutionary
conservation of this host defense pathway. We report here the cloning
of two novel human genes, TIL3 and TIL4 (Toll/IL-1R-like-3, -4) that
exhibit homology to both the leucine-rich repeat extracellular domains and the IL-1R-like intracellular domains of human and
Drosophila Toll. Northern analysis showed distinctly different
tissue distribution patterns with TIL3 expressed predominantly in
ovary, peripheral blood leukocytes, and prostate, and TIL4 expressed
primarily in peripheral blood leukocytes and spleen. Chromosomal
mapping by fluorescence in situ hybridization localized the TIL3 gene
to chromosome 1q41-42 and TIL4 to chromosome 4q31.3-32. Functional studies showed that both TIL3 and TIL4 are able to activate NF-B, though in a cell type-dependent fashion. Together with human
Toll, TIL3 and TIL4 encode a family of genes with
conserved structural and functional features involved in immune
modulation.
Blood, Vol. 91 No. 11 (June 1), 1998:
pp. 4020-4027
© 1998 by The American Society of Hematology.
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