The vasoactive hydrophilic amine histamine is the most important molecule released by mast cells. However, histamine's role in activating intracellular responses in HGFs (human gingival fibroblasts) has not been evaluated to date. In the present study, we investigated the effect of histamine and of Gram-negative [LPS (lipopolysaccharide)] and Gram-positive [LTA (lipoteichoic acid)] bacterial components on the modulation of the inflammatory response of HGFs. We incubated HGFs with histamine to determine whether this hydrophilic amine regulates overexpression of TLR2 (Toll-like receptor 2) and TLR4, which recognize LTA and LPS respectively. Our experiments demonstrated that histamine increases transcription and translation of TLR2 and TLR4. Incubation with LTA or LPS in the presence of histamine markedly increased expression of COX2 (cyclo-oxygenase 2) and synthesis of prostaglandin E2. These results suggest that histamine plays an important role in modulating the innate immune response, and likewise, that LTA and LPS regulate the adaptive immune response. The present study provides information about the regulation and expression of molecules that promote chronic inflammatory processes leading to the emergence of periodontitis and the consequent loss of the dental organ.