NF-kappaB independent activation of a series of proinflammatory genes by hydrogen sulfide.

A stress response has the potential to induce greater resistance to subsequent stress damage. We tested whether hydrogen sulfide (H(2)S), an important signaling molecule, also used therapeutically, and known for detrimental effects, might induce a protective stress response. Therefore, the response of fibroblast-like synoviocytes (FLS) treated with sodium hydrosulfide and mice exposed to H(2)S were examined. In both cases a profound and long lasting induction of the stress-response could be detected. However, despite the sustained presence of large levels of HO-1 and HSP-70, proinflammatory effects of exposure to IL-1beta or H(2)S itself were not ameliorated. On the contrary, at H(2)S concentrations significantly lower than 10 ppm-the current maximal allowable concentration of H(2)S in many countries-COX-2, IL-8, IL-1alpha, IL-1beta and TNFalpha were dose dependently elevated. Importantly, in FLS, short-term exposure to H(2)S resulted in the activation of all three MAPK. In addition, mitochondrial activity was also significantly impaired at relatively low H(2)S concentrations. The transcription factor NF-kappaB is essential for the activation of most proinflammatory genes. However, the data presented imply that H(2)S activates proinflammatory genes in FLS through non-NF-kappaB-dependent pathways. Stress proteins reportedly act by blocking NF-kappaB activation, a mechanism that would explain the inability of stress proteins to prevent H(2)S mediated inflammatory processes. The presented data, showing MAPK activation, NF-kappaB-independent activation of a number of proinflammatory genes and mitochondrial damage, help to provide a better understanding of the biological and pathophysiological effects of exposure to H(2)S.