A transient surge in cytokine expression, such as IL-8, IL-6, and TNF-α, is one of the early responses to sulfur mustard (SM) exposure in normal human epidermal keratinocytes (NHEK). We looked at the effects of over-expressing the anti-inflammatory cytokine interleukin 10 (IL-10) and the bona fide pro-inflammatory cytokine tumor necrosis factor –alpha (TNF-α) on the viability of SM-treated NHEK cells. TNF-α is known to participate in the inflammatory activities, cell toxicity, increased natural killer cell functions, and mediation of tumor cytotoxicity. IL-10, on the other hand, is a tightly regulated, immunosuppressive, anti-inflammatory cytokine that plays a central role in a number of human diseases such as inflammation, autoimmunity, and transplant rejection. It is believed that TNF-α activates the stress response transcription factor Nuclear Factor kappa B (NFκB), the main effector of the inducible anti-apoptotic response. NFκB is a cytoplasmic transcription factor that, upon activation, translocates into the nucleus and activates DNA transcription. It is known to be a major regulator of cytokine-induced gene expression, and several reports indicated that the activation of NFκB prevents apoptotic cell death induced by TNF-alpha, irradiation, and chemotherapeutic agents (1-3). In this study, we stably transfected SV-40-transformed HEK cells (tHEK) with either full-length human TNF-α cDNA or human IL-10 cDNA. We found that IL-10 and TNF-α play a central role in SM-induced cell death through modulation of IL-6 and IL-8 expression and NFκB DNA binding activity. We, therefore, identify IL-10 and TNF-α signal transduction pathways and their components as possible candidates for early therapeutic interventions against sulfur mustard-induced injury.