Differential patterns of ERK and STAT3 phosphorylation after sciatic nervetransection in the rat

Peripheral nerve injury induces a specific pattern of expression of growth factors and cytokines, which regulate injury responses and regeneration. Di stinct classes of growth factors and cytokines signal through specific intr acellular phosphorylation cascades. For example, the ERK phosphorylation ca scade mediates signaling through transmembrane tyrosine kinase receptors an d the JAK/STAT cascade mediates signaling through the GP130 receptor comple x. We tested whether specific phosphorylation patterns of ERK and STAT3 res ult from nerve injury and whether such phosphorylation correlates with the expression of specific growth factors and cytokines. At sites adjacent to a nerve transection, we observed that ERK phosphorylation peaked early, pers isted throughout 16 days, and was equally intense at proximal and distal si tes. In contrast, STAT3 phosphorylation peaked later than ERK but did not p ersist as long and was stronger in the proximal than in the distal segment adjacent to the injury. In addition, in distal segments further away from t he injury site, ERK became phosphorylated with a delayed time course, while STAT3 remained unphosphorylated. These patterns of phosphorylation correla ted well with the expression of neurotrophin and interleukin-6 mRNAs in the distal stump. In addition, we found that the pattern of SAPK phosphorylati on is similar to the pattern observed for STAT3, while the pattern of macro phage infiltration into the transected nerve was distinct from all the phos phorylation patterns observed. Together, these observations suggest that ER K activation is important in the establishment of a regeneration-promoting extracellular environment in the far distal stump of transected nerves and that STAT3 activation is important in the control of cellular responses clo se to the site of injury. (C) 2000 Academic Press.