Interleukin-10 is a potent suppressive factor that down-regulates cellular immune response via inhibition of the production of TH1 cytokines. Histamine shifts the TH1/TH2 balance from TH1 to TH2 cytokines making the effects of histamine on IL-10 secretion an important factor in this switch. This study was designed to assess the role of histamine in the regulation of IL-10 production and the involvement of PKA and STAT factors in this process. TH2 cells (D10.G4.1) and AKR/j splenocytes were pretreated with histamine at a concentration range of 10(-8)-10(-5) M for 1 h and then activated with PMA + ionomycin or anti-CD3 for 24 h. The supernatants were collected and tested for IL-10 content by ELISA. Histamine stimulated IL-10 production in TH2 cells in a dose-dependent manner that was reversed by both H1- and H2-receptor antagonists and by PKA inhibitors H8 and Rp-cAMPS. Tyrphostin also reversed the stimulation of IL-10 secretion by histamine, indicating that STAT factors were involved in this process. The up-regulation of IL-10 production by histamine in splenocytes was accompanied by inhibitory effects of histamine on IFN gamma production. The pretreatment of splenocytes with histamine in the presence of anti-IL-10 abrogated histamine-mediated inhibition of IFN gamma production suggesting that the effects of histamine on IFN gamma secretion were regulated by IL-10 in multi-cell system.