To determine whether IKK-NF-kappa B is activated either directly by compressive mechanical stress or by proinflammatory cytokines produced by MC3T3-E1 cells under compressive stress loading. MC3T3-E1 cells subjected to cyclic uniaxial compressive stress showed increased expression of proinflammatory cytokines and activation of the IKK-NF-kappa B signaling pathway with nuclear translocation of p65. Following treatment with antibodies to neutralize the action of the proinflammatory cytokines, IL-1 beta and IL-6, the activation of IKK-NF-kappa B signaling was notably inhibited in MC3T3-E1 cells subjected to force loading. IKK-NF-kappa B signaling in MC3T3-E1 cells may be activated by proinflammatory cytokines that are produced as a consequence of mechanical stress loading and not by direct compressive mechanical stress.