Differential regulation of MAP kinase signaling by pro- and antioxidant biothiols

Some biologically derived thiol-containing compounds have potential for health benefits whereas others elicit biochemical events leading to pathogenesis. Effects of two biothiols, α-lipoic acid (αLA), a therapeutic antioxidant, and homocysteine (Hcy), a risk factor for age-associated cardiovascular disease, on cell signaling events involving p44 and p42 MAP kinases (p44/42 MAPK) were evaluated in cell culture. Treatment of serum-deprived NIH/3T3 cells with Hcy (20 μM) resulted in the activation of p44/42 MAPK as determined by Western blot analysis using the phospho-specific p44/42 MAPK antibody. p44/42 MAPK phosphorylation was rapid and transient with maximal activation occurring at 10-30 min. Transient activation of p44/42 MAPK was also observed in response to treatment of serum-deprived cells with αLA. In cells grown in serum, serum-dependent p44/42 MAPK phosphorylation was transiently enhanced by Hcy or Hcy thiolactone, but inhibited by αLA. Thus, αLA and Hcy differentially influence signal transduction events depending on the state of cells. These observations may be important in understanding how some biothiols are associated with pathogenic events while others have potential as therapeutic agents.