Cis-uronic acid, a sunlight-induced immunosuppressive factor, activates immune suppression via the 5HT2A receptor

Jeffrey P. Walterscheid, Dat X. Nghiem, Nasser Kazimi, Leta K. Nutt, David McConkey, Mary Norval, Stephen E. Ullrich

Research output: Contribution to journalArticle

Abstract

Exposure to UV radiation induces skin cancer and suppresses the immune response. To induce immune suppression, the electromagnetic energy of UV radiation must be absorbed by an epidermal photoreceptor and converted into a biologically recognizable signal. Two photoreceptors have been recognized: DNA and trans-urocanic acid (UCA). Trans-UCA is normally found in the outermost layer of skin and isomerizes to the cis isomer upon exposure to UV radiation. Although UCA was identified as a UV photoreceptor years ago, and many have documented its ability to induce immune suppression, its exact mode of action remains elusive. Particularly vexing has been the identity of the molecular pathway by which cis-UCA mediates immune suppression. Here we provide evidence that cis-UCA binds to the serotonin [5-hydroxytryptamine (5-HT)] receptor with relatively high affinity (Kd = 4.6 nM). Anti-cis-UCA antibody precipitates radiolabeled 5-HT, and the binding is inhibited by excess 5-HT and/or excess cis-UCA. Similarly, anti-5-HT antibody precipitates radiolabeled cis-UCA, and the binding is inhibited by excess 5-HT or excess cis-UCA. Calcium mobilization was activated when a mouse fibroblast line, stably transfected with the human 5-HT2A receptor, was treated with cis-UCA. Cis-UCA-induced calcium mobilization was blocked with a selective 5-HT2A receptor antagonist. UV- and cis-UCA-induced immune suppression was blocked by antiserotonin antibodies or by treating the mice with 5-HT2A receptor antagonists. Our findings identify cis-UCA as a serotonin receptor ligand and indicate that the immunosuppressive effects of cis-UCA and UV radiation are mediated by activation of the 5-HT2A receptor.

Original languageEnglish (US)
Pages (from-to)17420-17425
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume103
Issue number46
DOIs
StatePublished - Nov 14 2006
Externally publishedYes

Fingerprint

NSC 153174
Urocanic Acid
Uronic Acids
Sunlight
Immunologic Factors
Immunosuppressive Agents
Receptor, Serotonin, 5-HT2A
Serotonin
Radiation
Serotonin 5-HT2 Receptor Antagonists
Serotonin Receptors
Antibodies

Keywords

  • Immune regulation
  • Inflammation
  • Serotonin
  • UV radiation

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

Cis-uronic acid, a sunlight-induced immunosuppressive factor, activates immune suppression via the 5HT2A receptor. / Walterscheid, Jeffrey P.; Nghiem, Dat X.; Kazimi, Nasser; Nutt, Leta K.; McConkey, David; Norval, Mary; Ullrich, Stephen E.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 103, No. 46, 14.11.2006, p. 17420-17425.

Research output: Contribution to journalArticle

Walterscheid, Jeffrey P. ; Nghiem, Dat X. ; Kazimi, Nasser ; Nutt, Leta K. ; McConkey, David ; Norval, Mary ; Ullrich, Stephen E. / Cis-uronic acid, a sunlight-induced immunosuppressive factor, activates immune suppression via the 5HT2A receptor. In: Proceedings of the National Academy of Sciences of the United States of America. 2006 ; Vol. 103, No. 46. pp. 17420-17425.
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AU - Nghiem, Dat X.

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AU - McConkey, David

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AB - Exposure to UV radiation induces skin cancer and suppresses the immune response. To induce immune suppression, the electromagnetic energy of UV radiation must be absorbed by an epidermal photoreceptor and converted into a biologically recognizable signal. Two photoreceptors have been recognized: DNA and trans-urocanic acid (UCA). Trans-UCA is normally found in the outermost layer of skin and isomerizes to the cis isomer upon exposure to UV radiation. Although UCA was identified as a UV photoreceptor years ago, and many have documented its ability to induce immune suppression, its exact mode of action remains elusive. Particularly vexing has been the identity of the molecular pathway by which cis-UCA mediates immune suppression. Here we provide evidence that cis-UCA binds to the serotonin [5-hydroxytryptamine (5-HT)] receptor with relatively high affinity (Kd = 4.6 nM). Anti-cis-UCA antibody precipitates radiolabeled 5-HT, and the binding is inhibited by excess 5-HT and/or excess cis-UCA. Similarly, anti-5-HT antibody precipitates radiolabeled cis-UCA, and the binding is inhibited by excess 5-HT or excess cis-UCA. Calcium mobilization was activated when a mouse fibroblast line, stably transfected with the human 5-HT2A receptor, was treated with cis-UCA. Cis-UCA-induced calcium mobilization was blocked with a selective 5-HT2A receptor antagonist. UV- and cis-UCA-induced immune suppression was blocked by antiserotonin antibodies or by treating the mice with 5-HT2A receptor antagonists. Our findings identify cis-UCA as a serotonin receptor ligand and indicate that the immunosuppressive effects of cis-UCA and UV radiation are mediated by activation of the 5-HT2A receptor.

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