NF-KappaB Independent Activation of a Series of Proinflammatory Genes by Hydrogen Sulfide

Abstract

A stress response has the potential to induce greater resistance to subsequent stress damage. We tested whether hydrogen sulfide (H₂S), 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 H₂S 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-1β or H₂S itself were not ameliorated. On the contrary, at H₂S concentrations significantly lower than 10 ppm—the current maximal allowable concentration of H₂S in many countries—COX-2, IL-8, IL-1α, IL-1β and TNFα were dose dependently elevated. Importantly, in FLS, short-term exposure to H₂S resulted in the activation of all three MAPK. In addition, mitochondrial activity was also significantly impaired at relatively low H₂S concentrations. The transcription factor NF-κB is essential for the activation of most proinflammatory genes. However, the data presented imply that H₂S activates proinflammatory genes in FLS through non-NF-κB-dependent pathways. Stress proteins reportedly act by blocking NF-κB activation, a mechanism that would explain the inability of stress proteins to prevent H₂S mediated inflammatory processes. The presented data, showing MAPK activation, NF-κB-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 H₂S.