Inhibition of activation‐induced changes in the structure of the T cell interleukin‐7 receptor by cyclosporin A and FK506

Abstract

We have recently shown that activation of T cells causes structural changes in the interleukin-7 receptor (IL-7R) (Foxwell et al. Int. Immunol. 1992, 4: 277). Unactivated cells expressed a receptor characterized as a cross-linked protein of 107-kDa whereas activated cells had reduced levels of this 107-kDa complex and now express a major cross-linked product of 93 kDa. These changes in receptor expression were concomitant with the acquisition of IL-7 growth responsiveness by activated T cells. In this study, the effect of the potent immunosuppressive agents cyclosporin A and FK506 on the activation-induced responsiveness to IL-7-driven proliferation and the concomitant changes in receptor structure have been investigated. Cyclosporin A and FK506 suppressed the expression of the 93-kDa complex and the loss of the 107-kDa complex on activated cells. The presence of exogenous IL-7 inhibited the effects of the drugs on IL-7R structure, allowing expression of the 93-kDa complex. Expression of the 93-kDa complex could also be induced either by ionomycin or phorbol esters. As observed for other T cell activation parameters, only those which induced a calcium signal (ionomycin) but not protein kinase C (phorbol esters) were sensitive to the drugs. In all studies, the expression of the 93-kDa complex correlated with the ability of cells to proliferate to IL-7, and thus these results further support the hypothesis that the 93-kDa form of the IL-7R is required to transmit the cytokine's growth signal. Moreover, these data suggest that activation-induced transcriptional events are required for the expression of the 93-kDa complex and the down-regulation of the 107-kDa complex. As reported for IL-2R and IL-4R, our data also show that the expression of another T cell growth factor receptor is sensitive to the effects of cyclosporin A and FK506. These observations also have important implications for reported cyclosporin A effects on the thymus where IL-7 can act as a growth factor for thymocytes.

Interleukin‐7. Biology and implications for dermatology

“…Itnmunoprecipitation studies and imtnunostaining of patticular T cell clones, which mainly express the p76 IL-7R, demonstrated that p76 kDa IL-7R is immunologically distinct from the p90 IL-7R (18), stiggesting that the p76 IL-7R is likely to be a product from a distinct gene. Activation of peripheral blood mononuclear cells (PBMC) in the ptesence of cyclosporin A or FK 506, which both inhibit IL-7-induced proliferation, repressed the expression of tbe p76 IL-7R but does not affect expression ofthe p90 IL-7R (19), These data imply that expression ofthe p76 1L-7R is necessary for IL-7-driven proliferation. The function of the ultra-low IL-7 receptor, which seetns to be a distinct entity, is currently unknown (15).…”

Functional interleukin-7 receptors (IL-7Rs) are expressed by marrow stromal cells: binding of IL-7 increases levels of IL-6 mRNA and secreted protein

“…7 Full-length human IL-7R has an expected molecular weight of 90 kd in reducing SDS-PAGE. 8 A 90-kd band of IL-7R was detected in HS-27a, primary LTCs of bone marrow, and PBMCs ( Figure 3A). However, immunoblotting for IL-7R protein in whole cell extracts of HS-27a occasionally revealed a smaller 30-kd band.…”