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Orthodontic malpractice or hyper-occlusal forces may aggravate periodontitis-induced destruction of periodontal tissues, but the specific mechanism remains unknown. In the present study, the combined effect of mechanical stress and tumor necrosis factor (TNF)-\u03b1 on the inflammatory response in human periodontal ligament stromal cells (hPDLSCs) was investigated.<\/jats:p><\/jats:sec><jats:sec><jats:title>Materials and methods<\/jats:title><jats:p>hPDLSCs from 5 healthy donors were treated with TNF-\u03b1 and\/or subjected to cyclic tensile strain (CTS) of 6% or 12% elongation with 0.1\u00a0Hz for 6- and 24\u00a0h. The gene expression of interleukin (IL)-6, IL-8 and cell adhesion molecules VCAM and ICAM was analyzed by qPCR. The protein levels of IL-6 and IL-8 in conditioned media was measured by ELISA. The surface expression of VCAM-1 and ICAM-1 was quantified by immunostaining followed by flow cytometry analysis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>TNF-\u03b1-induced IL-6 gene and protein expression was inhibited by CTS, whereas TNF-\u03b1-induced IL-8 expression was decreased at mRNA expression level but enhanced at the protein level in a magnitude-dependent manner. CTS downregulated the gene expression of VCAM-1 and ICAM-1 under TNF-\u03b1 stimulation, but the downregulation of the surface expression analyzed by flow cytometry was observed chiefly for VCAM-1.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Our findings show that mechanical force differentially regulates TNF-\u03b1-induced expression of inflammatory mediators and adhesion molecules at the early stage of force application. The effect of cyclic tensile strain is complex and could be either anti-inflammatory or pro-inflammatory depending on the type of pro-inflammatory mediators and force magnitude.<\/jats:p><\/jats:sec><jats:sec><jats:title>Clinical relevance<\/jats:title><jats:p>Orthodontic forces regulate the inflammatory mediators of periodontitis. 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