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Whereas the effects of interleukin (IL)-10 on several epithelial cell types are well established the capability of IL-10 to target keratinocytes (KC) is still a matter of debate. This, however, is of considerable importance, as IL-10 is a major anti-inflammatory, immunosuppressive cytokine with impact on the cutaneous homeostasis. Recently, IL-10 therapy has been proven to be clinically effective in psoriasis. Response to therapy is associated with normalization of typical parameters of keratinocyte pathology, but it is unclear whether this results from direct or indirect (secondary) effects. The purpose of the present study was to further investigate direct effects of IL-10 on keratinocytes and to address the reason for potential IL-10 unresponsiveness using keratinocytes such as the cell line HaCaT as well as primary foreskin keratinocytes. Using real time RT-PCR we demonstrated that IL-10 is neither able to induce its typical early gene product suppressor of cytokine signalling (SOCS) 3 nor to modulate the interferone (IFN)-gamma-induced expression of SOCS 1 and 3. Although flow cytometric analyses showed binding of biotin labelled IL-10 to HaCaT cells, blocking experiments indicated that this resulted from unspecific binding. Moreover, scatchard plot analyses excluded specific binding to primary KC and HaCaT cells. Finally, real time mRNA analyses and Western blot experiments demonstrated that the absence of any specific binding results from the absence of clear IL-10R1 (alpha chain) expression, whereas the IL-10R2 (beta chain) is strongly expressed. Our data indicates that IL-10 unresponsiveness of keratinocytes could be explained by the lacking of functional IL-10 receptor expression and suggest that any IL-10 effects on these cells observed are indirectly mediated.