Distinctive calcineurin-dependent (FK506-sensitive) mechanisms regulate the production of the CC chemokines macrophage inflammatory protein (MIP)-1 alpha, MIP-1 beta, and RANTES vs IL-2 and TNF-alpha by activated human T cells

Calcineurin (CaN) controls the production of multiple cytokines, including IL-2 and TNF-alpha, during T cell activation, However, its role in chemokin e production is unclear. Here, we used the CaN inhibitor FK506 to probe for the contribution of CaN in MIP-1 alpha, MIP-1 beta, and RANTES production at the protein and mRNA levels in human T cells stimulated via CD3/PMA or C D3/CD28, With both modes of activation, FK506 inhibited RANTES production o nly partially and late during a 3-day culture, whereas it suppressed both M IP-1 alpha and MIP-1 beta production throughout the culture. However, FK506 inhibition was more pronounced on MIP-1 beta than MIP-1 alpha, especially in CD3/CD28-activated T cells. Surprisingly, FK506 also significantly reduc ed MIP-1 beta induction by PMA alone. Furthermore, comparison with IL-2 and TNF-alpha revealed that both were more potently inhibited by the drug upon CD3/PMA or CD3/CD28 induction than either MIP-1 alpha or MIP-1 beta, These differences in FK506 sensitivity were also observed in CD4(+) and CD8(+) T cell subsets, Therefore, all three chemokines are affected by FK506 distin ctly from one another and from IL-2 and TNF-alpha, suggesting that CaN part icipates to different extents in the induction of these cytokines during T cell activation. Further evidence that this induction relies on distinctive mechanisms, depending on the cytokine, came from analyses of the kinetics and cycloheximide sensitivity of cytokine mRNA expression. (C) 1998 Academi c Press.