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Objectives: Oral mucosal macrophages (MØs) determine immune responses; maintaining tolerance whilst retaining the capacity to activate defences against pathogens. MØ responses are determined by two distinct subsets; pro-inflammatory M1- and anti-inflammatory/regulatory M2-MØs. Tolerance induction is driven by M2 MØs, whereas M1-like MØs predominate in inflammation, such as that exhibited in chronic Porphyromonas gingivalis (PG) periodontal infection. MØ responses can be suppressed to benefit either the host or the pathogen. Chronic stimulation by pathogen associated molecular patterns (PAMPs), such as LPS, is well established to induce tolerance. The aim of this study was to investigate the P. gingivalis-driven induction of and responsiveness to the suppressive, antiinflammatory cytokine, IL-10, by MØ subsets. Methods: M1- and M2-like MØs were generated in vitro from the THP-1 monocyte cell line by differentiation with PMA and Vitamin D3, respectively. MØ subsets were stimulated by PG-LPS in the presence or absence of IL-10. Results: PG-LPS differentially induced IL-10 secretion and endogenous IL-10 activity in M1- and M2-like subsets. In addition, these subsets exhibited differential sensitivity to IL-10-mediated suppression of TNFα, where M2 MØs where sensitive to IL-10 and M1 MØs were refractory to suppression. In addition, this differential responsiveness to IL-10 was independent of IL-10-binding and expression of the IL-10 receptor signal transducing subunit, IL-10Rβ, but was in fact dependent on activation of STAT-3. Conclusion: P.gingivalis selectively tolerises regulatory M2 MØs with little effect on pro-inflammatory M1 MØs; differential suppression facilitating immunopathology at the expense of immunity. [ABSTRACT FROM AUTHOR]