Porphyromonas gingivalis lipopolysaccharide (LPS) (strain W50) interacts with Toll-like receptor 2 (TLR-2) leading to cytokine expression and inflammation, and thereby plays a key role in the pathogenesis of periodontal disease. The aims of this study were to investigate gene expression of key regulatory mediators of innate immune responses in a human monocytic cell line (THP-1) to P. gingivalis LPS and to compare these results with those obtained using the TLR-4 ligand, Escherichia coli LPS. Custom-made Taqman low-density arrays were used for expression profiling of 45 different cytokine-related genes. Both types of LPS highly up-regulated interleukin (IL)-1alpha and IL-1beta, IL-18 receptor (IL-18R), IL-18R accessory protein and IL-1 family (IL-1F)9. Expression levels of IL-1F6, IL-1F7 and caspase-1 were unaltered by either LPS. Genes for tumour necrosis factor-alpha, IL-6, leukaemia inhibitory factor and IL-32 were also highly induced by both LPS. For a subset of genes, including CXC chemokine ligand 5 (CXCL5), expression was induced only by E. coli LPS or was up-regulated more highly by E. coli compared with P. gingivalis LPS in THP-1 monocytes. A similar expression pattern was also observed in dendritic cells. Analysis of signalling pathways which lead to CXCL5 expression indicated that the mechanisms underpinning the differential responses did not involve the recruitment of different adaptor proteins by TLR-2 and TLR-4, and therefore occur downstream of the receptor-adaptor complex. We conclude that differences in signalling pathways activated by TLR-2 and TLR-4 ligands lead to differential innate immune responses which may be important in polymicrobial diseases such as periodontal disease.