(Verbatim) In addition to being a complete carcinogen, UV exposure is immune suppressive. Experiments with animals and studies with biopsy proven skin cancer patients have indicated that the immune suppression induced by UV exposure is a major risk factor for skin cancer induction. Because of the association between the carcinogenic and immune suppressive effects of UV radiation, it is critically important to determine the mechanisms involved in the induction of immune suppression. The hypothesis tested states that the release of immunomodulatory cytokines in response to UV exposure is responsible for inducing systemic immune suppression. During the initial funding period evidence was provided supporting this hypothesis. Following UV exposure, a cytokine cascade, including prostaglandin E2 (PGE2) interleukin (IL)-4 and IL-l0 is activated. The production of PGE2 is key in that a selective cyclooxygenase-2 inhibitor blocks both the production of serum IL-4 and 10 and abrogates UV-induced immune suppression. Moreover, evidence was generated to show that one consequence of UV irradiation is an alteration of dendritic cell production of IL-12. Rather than secreting biologically active ILl2p70, UV exposure induces the release of the immune suppressive IL-l2p40 homodimer. The focus of the present proposal is to elucidate the mechanisms involved in the production and suppressive activity of UV-induced cytokines.
The Specific Aims of the present proposal are: 1) Determine the mechanism(s) by which cytokines are induced in the skin following UV exposure. Are UV-responsive elements in the promoter region of the cyclooxygenase gene directly affected by UV radiation or are co-factors, such as histamine required? 2) What is the cellular source of the UV-induced serum IL-4? Is cytokine secretion by circulating T cells, mast cells and/or NK1. I cells involved in transmitting the suppressive signal from the skin to immune elements? 3) Is the inability of dendritic cells from UV-irradiated mice to active Th 1 cells due to secretion of the IL- l2p4O homodimer, a receptor antagonist reported to block activation of T helper (Th) I cells, while allowing Th2 cell activation? Is UV-induced PGE2, or IL-4 or IL-l0 involved in the production of the IL-12p40 homodimer? The long term goal of this research is to determine the mechanisms involved in the induction of immune suppression following UV exposure, concentrating on the role of cytokines. A better understanding of the mechanisms involved may help with the design of rational approaches to block the induction of immune suppression, thereby reducing one of the major risk factors for skin cancer induction.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA075575-12
Application #
6895905
Study Section
General Medicine A Subcommittee 2 (GMA)
Program Officer
Pelroy, Richard
Project Start
1991-09-30
Project End
2007-05-31
Budget Start
2005-06-01
Budget End
2007-05-31
Support Year
12
Fiscal Year
2005
Total Cost
$236,250
Indirect Cost
Name
University of Texas MD Anderson Cancer Center
Department
Microbiology/Immun/Virology
Type
Other Domestic Higher Education
DUNS #
800772139
City
Houston
State
TX
Country
United States
Zip Code
77030
Byrne, Scott N; Limon-Flores, Alberto Y; Ullrich, Stephen E (2008) Mast cell migration from the skin to the draining lymph nodes upon ultraviolet irradiation represents a key step in the induction of immune suppression. J Immunol 180:4648-55
Sreevidya, Coimbatore S; Khaskhely, Noor M; Fukunaga, Atsushi et al. (2008) Inhibition of photocarcinogenesis by platelet-activating factor or serotonin receptor antagonists. Cancer Res 68:3978-84
Fukunaga, Atsushi; Khaskhely, Noor M; Sreevidya, Coimbatore S et al. (2008) Dermal dendritic cells, and not Langerhans cells, play an essential role in inducing an immune response. J Immunol 180:3057-64
Ullrich, Stephen E (2007) Sunlight and skin cancer: lessons from the immune system. Mol Carcinog 46:629-33
Ullrich, Stephen E; Nghiem, Dat X; Khaskina, Polina (2007) Suppression of an established immune response by UVA--a critical role for mast cells. Photochem Photobiol 83:1095-100
Wolf, Peter; Nghiem, Dat X; Walterscheid, Jeffrey P et al. (2006) Platelet-activating factor is crucial in psoralen and ultraviolet A-induced immune suppression, inflammation, and apoptosis. Am J Pathol 169:795-805
Matsumura, Yumi; Byrne, Scott N; Nghiem, Dat X et al. (2006) A role for inflammatory mediators in the induction of immunoregulatory B cells. J Immunol 177:4810-7
Walterscheid, Jeffrey P; Nghiem, Dat X; Kazimi, Nasser et al. (2006) Cis-urocanic acid, a sunlight-induced immunosuppressive factor, activates immune suppression via the 5-HT2A receptor. Proc Natl Acad Sci U S A 103:17420-5
Ullrich, Stephen E (2005) Mechanisms underlying UV-induced immune suppression. Mutat Res 571:185-205
Ramos, Gerardo; Kazimi, Nasser; Nghiem, Dat X et al. (2004) Platelet activating factor receptor binding plays a critical role in jet fuel-induced immune suppression. Toxicol Appl Pharmacol 195:331-8

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