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.