Ultraviolet Light (UV) Regulation of the TNF Family Decoy Receptors DcR2 and DcR3 in Human Keratinocytes

Abstract

Background:

Several additional members of the tumor necrosis factor (TNF) receptor family were recently identified. The existence of such receptors, which may play distinct and unique regulatory roles, suggests that complex regulatory mechanisms are involved in apoptosis.

Objective:

This study examines the expression of several members of the TNF receptor family in human keratinocytes exposed to ultraviolet B (UVB) irradiation.

Methods:

Human keratinocytes were exposed to increasing doses of UVB, total RNA was harvested, and a quantitative RNase protection assay was performed.

Results:

Decoy receptor-3 (DcR3), a nonfunctional receptor that binds to Fas ligand (FasL), was constitutively expressed at high level in keratinocytes but decreased rapidly in cells exposed to UVB. Decoy receptor-2 (DcR2), a nonfunctional receptor that binds to TNF-related apoptosis-inducing ligand (TRAIL)/APO-2L, showed the opposite expression pattern. DcR2 was undetectable in unirradiated keratinocytes and was markedly up-regulated after exposure to UVB. Although the response showed significant delays at higher UVB doses, the patterns observed for DcR3 and DcR2 were consistent in this set of experiments.

Conclusion:

We conclude that UVB regulates expression of these two TNF decoy receptors in keratinocytes. This pathway may represent a novel mechanism for regulation of apoptosis in the skin.

Get full access to this article

View all access options for this article.

References

Thompson

. Apoptosis in the pathogenesis and treatment of disease. Science 1995; 267:1456–1462.

Nagata

. Apoptosis by death factor. Cell 1997; 88:355–365.

Wiley

Schooley

Smolak

. Identification and characterization of a new member of the TNF family that induces apoptosis. Immunity 1995; 3:673–682.

Leverkus

Yaar

Gilchrest

. Fas/Fas ligand interaction contributes to UV-induced apoptosis in human keratinocytes. Exp Cell Res 1997; 232:255–262. DOI: 10.1006/excr.1997.3514

Rehemtulla

Hamilton

Chinnaiyan

. Ultraviolet radiation-induced apoptosis is mediated by activation of CD-95 (Fas/APO1). J Biol Chem 1997; 272:25783–25786. DOI: 10.1074/jbc.272.41.25783

Aragane

Kulms

Metze

. Ultraviolet light induces apoptosis via direct activation of CD95 (Fas/APO-1) independently of its ligand CD95L. J Cell Biol 1998; 140:171–182.

Pan

O'Rourke

Chinnaiyan

. The receptor for the cytotoxic ligand TRAIL. Science 1997; 276:111–113. DOI: 10.1126/science.276.5309.111

Walczak

Degli–Esposti

Johnson

. TRAIL-R2: A novel apoptosis-mediating receptor for TRAIL. EMBO J 1997; 16:5386–5397. DOI: 10.1093/emboj/16.17.5386

Pan

Wei

. An antagonist decoy receptor and a death domain-containing receptor for TRAIL. Science 1997; 277:815–818. DOI: 10.1126/science.277.5327.815

10.

Sheridan

Marsters

Pitti

. Control of TRAIL-induced apoptosis by a family of signaling and decoy receptors. Science 1997; 277:818–821. DOI: 10.1126/science.277.5327.818

11.

Marsters

Sheridan

Pitti

. A novel receptor for AP02L/TRAIL contains a truncated death domain. Curr Biol 1997; 7:1003–1006.

12.

Pitti

Marsters

Lawrence

. Genomic amplification of a decoy receptor for Fas ligand in lung and colon cancer. Nature 1998; 396:699–703. DOI: 10.1038/25387

13.

Kwon

. A newly identified member of tumor necrosis factor receptor superfamily (TR6) suppresses LIGHT-mediated apoptosis. J Biol Chem 1999; 274:13733–13736. DOI: 10.1074/jbc.274.20.13733

14.

Emery

McDonnell

Burke

. Osteoprotegerin is a receptor for the cytotoxic ligand TRAIL. J Biol Chem 1998; 273:14363–14367. DOI: 10.1074/jbc.273.23.14363

15.

Sheikh

Antinore

Huang

. Ultraviolet-irradiation-induced apoptosis is mediated via ligand independent activation of tumor necrosis factor receptor 1. Oncogene 1998; 17:2555–2563.

16.

Hill

Ouhtit

Loughlin

. Fas ligand: A sensor for DNA damage critical in skin cancer etiology. Science 1999; 285:898–900. DOI: 10.1126/science.285.5429.898

17.

Devary

Rosette

DiDonato

. NF-kappa B activation by ultraviolet light not dependent on a nuclear signal. Science 1993; 261:1442–1445.

18.

Kulms

Poppelmann

Yarosh

. Nuclear and cell membrane effects contribute independently to the induction of apoptosis in human cells exposed to UVB radiation. Proc Natl Acad Sci USA 1999; 96:7974–7979. DOI: 10.1073/pnas.96.14.7974

19.

Tron

Trotter

Tang

. p53-regulated apoptosis is differentiation dependent in ultraviolet B-irradiated mouse keratinocytes. Am J Pathol 1998; 153:579–585.

20.

Mitchell

. Decreased DNA repair but normal apoptosis in ultraviolet-irradiated skin of p53-transgenic mice. Am J Pathol 1996; 148:1113–1123.

21.

Werninghaus

Handjani

Gilchrest

. Protective effect of alpha-tocopherol in carrier liposomes on ultraviolet-mediated human epidermal cell damage in vitro. Photodermatol Photoimmunol Photomed 1991; 8:236–242.

22.

Sambrook

Fritsch

Maniatis

. Synthesis of RNA probes by in vitro transcription of double-stranded DNA templates by bacteriophage DNA-dependent RNA polymerases. In: Ford

Nolan

Ferguson

, eds. Molecular Cloning: A Laboratory Manual. New York: Cold Spring Harbor Laboratory Press, 1989, pp 10.27–10.37.

23.

Gilman

. Ribonuclease protection assay. In: Ausubel

Brent

Kingston

, eds. Current Protocols in Molecular Biology. New York: John Wiley and Sons, 1993, pp 4.7.1–4.7.8.

24.

Sheikh

Burns

Huang

. p53-dependent and -independent regulation of the death receptor KILLER/DR5 gene expression in response to genotoxic stress and tumor necrosis factor alpha. Cancer Res 1998; 58:1593–1598.

25.

Sheikh

Huang

Fernandez-Salas

. The antiapoptotic decoy receptor TRID/TRAIL-R3 is a p53-regulated DNA damage-inducible gene that is overexpressed in primary tumors of the gastrointestinal tract. Oncogene 1999; 18:4153–4159.

26.

Ashkenazi

Dixit

. Death receptors: Signaling and modulation. Science 1998; 281:1305–1308.

27.

Suda

Takahashi

Golstein

. Molecular cloning and expression of the Fas ligand, a novel member of the tumor necrosis factor family. Cell 1993; 75:1169–1178.

28.

Ashkenazi

Pai

Fong

. Safety and antitumor activity of recombinant soluble Apo2 ligand. J Clin Invest 1999; 104:155–162.

29.

Bai

Connolly

Metzker

. Overexpression of M68/DcR3 in human gastrointestinal tract tumors independent of gene amplification and its location in a fourgene cluster. Proc Natl Acad Sci USA 2000; 97:1230–1235. DOI: 10.1073/pnas.97.3.1230

30.

Leverkus

Neumann

Mengling

. Regulation of tumor necrosis factor-related apoptosis-inducing ligand sensitivity in primary and transformed human keratinocytes. Cancer Res 2000; 60:553–559.