Identification of Novel Activities of Immunomodulatory Drugs: Cytoskeleton Reorganization through Modulation of Rho GTPases

Immunomodulatory drugs including the IMiDs®, lenalidomide, and pomalidomide represent a novel class of compounds that have both anti-cancer and anti-inflammatory properties. While many studies have demonstrated that IMiDs have broad in vitro and in vivo biological activities including antiangiogenesis, inhibition of TNFa expression, enhancement of antitumor immunity, and induction of IL-2 in T cells, the molecular mechanism through which these drugs exert their effects is largely undefined. In primary human monocytes, IMID1 selectively activated RhoA and Rac1, but not Cdc42 or Ras. Importantly, the activation of these GTPases occurred immediately following treatment with IMID1 in the absence of any costimulation. Consistent with the activation of Rho GTPases, we found that IMID1enhanced F-actin formation, stabilized microtubules, and increased monocyte cell migration, all of which were blocked by selective inhibitors of ROCK1, a downstream effector of RhoA or Rac1. Finally, we demonstrated that IMID1 was able to regulate the activity of Rho GTPases and formation of F-actin in primary human T cells similarly as it did in monocytes, and showed that the activation of RhoA was essential for IMID1-induced IL-2 expression in T cells. In conclusion, these studies demonstrate a novel and acute molecular activity from IMiDs mediated via Rho GTPases. Activation of Rho by IMiDs and the resulting effect on cytoskeletal reorganization may represent a critical mechanism by which IMiDs function as therapeutic immunomodulatory agents.