FK506 inhibits antigen receptor-mediated induction of c-rel in B and T lymphoid cells.

Abstract

SunllTlaryStimulation of B and T cells via the antigen receptor, by phorbol ester or by phorbol ester and ionomycin, leads to nuclear translocation of the inducible transcription factor NF-KB, comprising the p50 and p65 re/-related polypeptides. In this report we show that c-tel is a component of the antigen receptor-induced xB binding proteins in both B and T cells. Whereas NF-~cB can be induced by phorbol ester alone, optimal induction of c-tel requires stimulation by both phorbol ester and ionomycin, the dual signal that is necessary for proliferation of untransformed lymphocytes. Furthermore, c-tel induction is blocked by the immunosuppressive drug FK506 that is known to inhibit B and T cell activation, c-rel-dependent transactivation of the interleukin-2 receptor ot chain (Ib2Rot) promoter is augmented by coexpression of calcineurin, suggesting the involvement of a calcineurin-dependent intracellular pathway. Our results identify c-tel as a target of immunosuppressive agents and illustrate the similarity of activation pathways in both B and T ceils. Stim. ulation of B and T cells via the antigen receptor triggers a signaling cascade that results in clonal cell proliferation characteristic of the immune response. Alteration of the resting program of gene expression is brought about by inducible nuclear factors that transmit the signal generated at the plasma membrane to the cell nucleus. Several transcription factors have been identified that are induced in response to antigen receptor cross-linking, or its pharmacologic equivalent, the combined action of phorbol esters and calcium ionophore. We, and others, have shown that antigenreceptor cross-linking on both B and T cells induces the factors NF-KB, AP-1, and cAMP response element-binding protein (CREB) (1)(2)(3)(4). However, these proteins can be induced by the action of phorbol ester alone on these cells, a signal that is not sufficient to induce proliferation. A notable exception is NF-AT, a nuclear factor present in activated T cells, whose induction requires the dual signal of phorbol ester and ionomycin (5). We have recently shown that both signals are also required to induce an indistinguishable DNA-binding protein in B cells, indicating that NF-AT should be regarded more generally as a factor of activated lymphoid ceils (6). Because it is likely that proteins that are induced in response to the complete proliferative signal will play a critical role in normal and aberrant immune responses, it is essential to identify factors that satisfy this criterion.The immunosuppressive drugs cyclosporin A and FKS06 block B and T cell proliferation (7-9). The intracellular pathway of drug action in T cells has been recently elucidated. Both drugs bind to distinct cytosolic receptors and the drug receptor complexes inhibit the enzymatic activity of the calcium and cahnodulin-dependent serine/threonine phosphatase, calcineurin (10-13). NF-ATp/c, the preexisting cytoplasmic component of NF-AT (14-16), has been implicated as a direct target of calcineurin (17,18). ...

Inhibitors of NF-κB signaling: 785 and counting

“…That is, FK506 can specifically block c-Rel nuclear translocation (but not p50/RelA) after treatment of cells with phorbol esters and ionomycin Venkataraman et al, 1995). Therefore, the antiproliferative effects of FK506 in T cells results from inhibition of NF-kB, which consequently blocks transcription of the IL-2 and IL-2 receptor genes by interfering with the induction of c-Reldependent transcription of their promoters (Serfling et al, 1995;Venkataraman et al, 1995). Interestingly, the effectiveness of topical administration of FK506 ointment in keratinocytes correlates with its anti-NF-kB activity (Lan et al, 2005), suggesting that inhibition of NF-kB may be responsible for FK506's effectiveness in psoriasis.…”

“…However, unlike CsA, the inhibitory effect of tacrolimus on NF-kB appears, in some cases, to be specific for c-Rel, among the NF-kB family members. That is, FK506 can specifically block c-Rel nuclear translocation (but not p50/RelA) after treatment of cells with phorbol esters and ionomycin Venkataraman et al, 1995). Therefore, the antiproliferative effects of FK506 in T cells results from inhibition of NF-kB, which consequently blocks transcription of the IL-2 and IL-2 receptor genes by interfering with the induction of c-Reldependent transcription of their promoters (Serfling et al, 1995;Venkataraman et al, 1995).…”

Diverse agents act at multiple levels to inhibit the Rel/NF-κB signal transduction pathway

“…These molecules were originally used as inhibitors of serine proteases, but were also found to act as proteasome Palombella et al, 1994;Grisham et al, 1999;Jobin et al, 1998a ALLnL (N-acetyl-leucinyl-leucynil-norleucynal Okamoto et al, 1994;Venkataraman et al, 1995Deoxyspergualin Tepper et al, 1995 Protease inhibitors inhibitors and to be more potent than are their aldehyde analogs (Grisham et al, 1999;Iqbal et al, 1995). An indirect method of blocking proteasomemediated degradation of IkB is by inhibiting the ubiquitin ligase that acts on IkB.…”

“…FK506 also has been reported to block NF-kB DNA binding in Jurkat T cells stimulated with phorbol ester (Okamoto et al, 1994). Therefore, the antiproliferative e ects of FK506 in T cells results from inhibition of Rel/NF-kB, which consequently blocks transcription of the IL-2 and IL-2 receptor genes by interfering with the induction of kB site-dependent transcription of their promoters (Ser¯ing et al, 1995;Venkataraman et al, 1995).…”

Suppression of Monocyte Chemoattractant Protein 1, But Not IL-8, by Alprazolam: Effect of Alprazolam on c-Rel/p65 and c-Rel/p50 Binding to the Monocyte Chemoattractant Protein 1 Promoter Region

“…It was clear that Rel is a positive or negative regulator of transcription in macrophages and that Rel has distinct roles in different macrophage populations. Venkataraman et al showed that c-Rel is a component of the Ag receptor-induced, B binding proteins in both B and T cells (27). Moreover, there is evidence that c-Rel contributes to the survival of nerve growth factor-dependent sympathetic neurons (28), the human 12-lipoxygenase gene (29), and c-myc gene transcription (30).…”