Background and Objective Porphyromonas gingivalis infection is strongly associated with periodontitis. Although P. gingivalis is known to elicit a strong inflammatory response, details of that remain fragmentary. To understand the local response to P. gingivalis, primary cell lines derived from mouse gingival tissues were exposed to P. gingivalis or E. coli lipopolysaccharide (LPS), and cytokine production for interleukin-6 (IL-6) and tumor necrosis factor-α (TNFα were measured. CCL25 gene expression was measured by real-time PCR. Cells stimulated with combinations of IL-6, soluble IL-6 receptor (sIL-6R), and/or soluble gp130 (sgp130) were assayed for CCL2 and TNFα secretion. Methods Primary cell lines were generated from mouse gingival tissues. Enzyme-linked assays were used to determine cytokine levels, and real-time PCR was used to quantify CCL25 gene expression. Results Exposure to P. gingivalis but not E. coli LPS resulted in significantly elevated levels of both IL-6 and TNFα, and P. gingivalis LPS-stimulation also upregulated CCL25 gene expression. In one of three experiments, IL-6 induced CCL2 secretion, whereas IL-6 with sIL-6R induced CCL2 secretion in all three experiments, suggesting that both direct IL-6 signaling and IL-6 trans-signaling may be involved. However, because sgp130 did not inhibit trans-signaling, and because direct stimulation of gingival cells with sgp130 resulted in CCL2 secretion, the possibility exists that sgp130 forms binary complexes with soluble IL-6R that promote direct IL-6 stimulation. Conclusion These findings define a pathway in which exposure of gingival cells to P. gingivalis induces the release of IL-6 and TNFα; IL-6 in turn induces CCL2 secretion.