Nonsteroidal anti-inflammatory drugs suppress T-cell activation by inhibiting p38 MAP kinase induction

In addition to antagonizing inflammation by inhibit- ing the activity of cyclooxygenases (COX), nonsteroidal anti-inflammatory drugs (NSAID) block T-cell activa- tion. The immunosuppressant activity of NSAID corre- lates with their ability to block transcription factors required for the expression of inducible response genes triggered by T-cell antigen receptor (TCR) engagement. Whereas the inhibition of nuclear factor-B by aspirin and sodium salicylate can be partly accounted for by their binding to IB kinase-, the broad range of tran- scriptional targets of NSAID suggests that the products of COX activity might affect one or more among the early steps in the TCR-signaling cascade. Here we show that the inhibition of NF-AT activation by NSAID corre- lates with a selective inhibition of p38 MAP kinase in- duction. The suppression of TCR-dependent p38 activa- tion by NSAID can be fully overcome by prostaglandin E2, underlining the requirement for COX activity in p38 activation. Furthermore, the inhibition of COX-1 results in defective induction of the COX-2 gene, which behaves as an early TCR responsive gene. The data identify COX-1 and COX-2 as integral and sequential components of TCR signaling to p38 and contribute to elucidate the molecular basis of immunosuppression by NSAID.