LFA‐1 engagement‐induced T cell cytokine mRNA stabilization involves a Rac, p38 MAP kinase, MK2 cascade

Abstract

We have demonstrated that engagement of the β2 integrin, lymphocyte function‐associated antigen‐1 (LFA‐1), results in stabilization of Th1 mRNA transcripts containing 3′‐untranslated region AU‐rich elements (AREs), including those encoding IFN‐γ and TNF‐α, requiring an induced nuclear‐to‐cytosolic translocation of the ARE‐binding protein HuR. We now show that LFA‐1 engagement by its ligand, ICAM‐1, results in PI‐3 kinase (PI3K)‐dependent activation of the Rho family GTPases Rac‐1 and ‐2 in HSB‐2 T cells. Pretreatment with the PI3K inhibitor LY294002, or Rac‐1/2 knockdown, resulted in attenuation of LFA‐1‐induced TNF‐α mRNA stabilization. LFA‐1‐stimulated HuR translocation and IFN‐γ mRNA stabilization was absent in T cells isolated from the Rac target MKK3 gene‐deleted mice. Moreover, LFA‐1‐stimulated activation of p38 and its target, MK2, are required for induced TNF‐α mRNA stabilization, which was abrogated by the p38 inhibitor SB203580, and absent in T cells obtained from MK2−/− mice. These results demonstrate that a sequentially activated PI3K, Rac, MKK3, p38, MK2 cascade drives T cell LFA‐1‐induced Th1 cytokine mRNA stabilization. (Supported by NIH grant RO1 HL043331 and the Raymond and Beverly Sackler Foundation)