Phototherapy is routinely used for the treatment of various skin conditions and targeted therapy of superficial cancers. However, the molecular mechanisms behind their biological effects and the need for efficacy enhancing photosensitizers are not well addressed. Particularly, not much is known about the inherent effect of light from the visible spectrum on cytokine release and its downstream effects in keratinocytes and immune cells located in skin and therefore exposed to light. To address this, we delivered calibrated doses of well-defined light qualities (380 to 660 nm) to cocultures of human keratinocytes and macrophage/dendritic cells in the absence or presence of the commonly used photosensitizer 8-methoxypsoralen (8-MOP). The experiments identified IL-4 as a key effector cytokine released by this coculture model with need for 8-MOP in the UVA1/blue (380 nm) and no requirement for photosensitizer in the red light spectrum (627 nm). 3D organotypic skin cultures treated with IL-4 showed thickening of the epidermal layer and delayed differentiation. However unlike IL-4 and UVA1/blue light treatment, red light did not reduce the expression of keratinocyte differentiation markers or increase signs of photo-oxidative damage. This supports the application of isolated red light as a possible alternative for photo-immunotherapy without need for additional photosensitizers.