title: Serotonin signalling is crucial in the induction of PUVA-induced systemic suppression of delayed-type hypersensitivity but not local apoptosis or inflammation of the skin.
abstract: Psoralen and UVA (PUVA) has immunosuppressive and proapoptotic effects, which are thought to be responsible alone or in combination for its therapeutic efficacy. However, the molecular mechanism by which PUVA mediates its effects is not well understood. Activation of the serotonin (5-hydroxytryptamine, 5-HT) pathway has been suggested to be involved in the modulation of T-cell responses and found to mediate UVB-induced immune suppression. In particular, the activation of the 5-HT2A receptor has been proposed as one mechanism responsible for UV-induced immune suppression. We therefore hypothesized that 5-HT may play a role in PUVA-induced effects. The model of systemic suppression of delayed-type hypersensitivity (DTH) to Candida albicans was used to study immune function after exposure of C3H and KIT(W) (-Sh/W-Sh) mice to a minimal inflammatory dose of topical PUVA. The intra-peritoneal injection of the 5-HT2 receptor antagonist ketanserin or cyproheptadine or an anti-5-HT antibody immediately before PUVA exposure entirely abrogated suppression of DTH but had no significant effect on inflammation, as measured by swelling and cellular infiltration of the skin, and apoptosis as determined by the number of sunburn cells in C3H mice. Importantly, the systemic injection of 5-HT recapitulated PUVA immune suppression of DTH but did not induce inflammation or apoptosis in the skin. KIT(W) (-Sh/W-Sh) mice (exhibiting myelopoietic abnormalities, including lack of 5-HT-containing mast cells) were resistant to PUVA-induced suppression of DTH but not local skin swelling. Thus, this points towards a crucial role of 5-HT signalling in PUVA-induced immune suppression but not inflammation or apoptosis in situ in the skin.
authors.affiliation: Research Unit for Photodermatology, Department of Dermatology, Medical University of Graz, Graz, Austria.
authors.forename: Peter
authors.initials: P
authors.lastname: Wolf
authors.affiliation: Cellular Photoimmunology Group, Infectious Diseases and Immunology, Sydney Medical School, The Charles Perkins Centre at The University of Sydney, Sydney, NSW, Australia.
authors.forename: Scott N
authors.initials: SN
authors.lastname: Byrne
authors.affiliation: Laboratory of Immunology, Faculty of Medicine, Universidad Autonoma de Nuevo León, Monterrey, Mexico.
authors.forename: Alberto Y
authors.initials: AY
authors.lastname: Limon-Flores
authors.affiliation: Institute for Pathology, Medical University of Graz, Graz, Austria.
authors.forename: Gerald
authors.initials: G
authors.lastname: Hoefler
authors.affiliation: Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Stephen E
authors.initials: SE
authors.lastname: Ullrich
mesh_terms: D000818:Animals; D017209:Apoptosis; D005260:Female; D006968:Hypersensitivity, Delayed / Q000188:drug therapy / Q000378:metabolism*; D007249:Inflammation / Q000378:metabolism; D008407:Mast Cells / Q000502:physiology; D008809:Mice, Inbred C3H; D011701:PUVA Therapy; D012701:Serotonin / Q000378:metabolism*
chemical_list: D012701:Serotonin
keywords: PUVA; immune suppression; mast cells; serotonin; ultraviolet radiation