Differential Inhibition of the T Cell Activation Pathway by Dexamethasone and Cyclosporine

Furue, Masutaka; Kawakami, Yuko; Kawakami, Toshiaki; Katz, Stephen I.

doi:10.1097/00007890-199003000-00017

Cited by 14 publications

(4 citation statements)

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“…It is also important to emphasize that this proposal does not conflict with the concept that DEX affects the function of T cells. As predicted by reports from many investigators (31,34,35), DEX did inhibit IL-2 secretion by T cells in our experimental system. Although somewhat conflicting results have been reported with respect to the impact of GCs on the expression (and function) of the IL-2R complex (35-40), we observed that DEX had only a negligible effect on DC-stimulated expression of CD25 (␣ chain).…”

Section: Discussionsupporting

confidence: 91%

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A novel mechanism of glucocorticoid-induced immune suppression: the inhibiton of T cell-mediated terminal maturation of a murine dendritic cell line.

Kitajima

Ariizumi²,

Bergstresser³

et al. 1996

J. Clin. Invest.

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Section: Discussionsupporting

confidence: 91%

“…For instance, DEX has been shown to inhibit Ag-presenting celldependent activation of T cells, but not Ag-presenting cellindependent activation, as is triggered by phorbol esters and calcium ionophores (31). DEX is also known to downregulate the costimulatory capacity of Langerhans cells (32).…”

Section: Discussionmentioning

confidence: 99%

A novel mechanism of glucocorticoid-induced immune suppression: the inhibiton of T cell-mediated terminal maturation of a murine dendritic cell line.

Kitajima

Ariizumi²,

Bergstresser³

et al. 1996

J. Clin. Invest.

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“…In some experiments, BMMC depleted of IL-3 for 16 to 18 h were incubated with 100 ng of either mouse recombinant IL-3 or mouse SCF per ml for various lengths of time before cell lysis. Growth stimulation was monitored by [3H]thymidine uptake as described previously (11). In one experiment (see Fig.…”

Section: Methodsmentioning

confidence: 99%

Tyrosine phosphorylation and activation of Bruton tyrosine kinase upon Fc epsilon RI cross-linking.

et al. 1994

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Tyrosine phosphorylation of several cellular proteins is one of the earliest signaling events induced by cross-linking of the high-affinity receptor for immunoglobulin E (FcERI) on mast cells or basophils. Tyrosine kinases activated during this process include the Src family kinases, Lyn, c-Yes, and c-Src, and members of another subfamily, Syk and PTK72 (identical or highly related to Syk). Recently, some of us described two novel tyrosine kinases, Emb and Emt, whose expression was limited to subsets of hematopoietic cells, including mast cells. Emb turned out to be identical to Btk, a gene product defective in human X-linked agammaglobulinemia and in X-linked immunodeficient (xid) mice. Here we report that FcrRI cross-linking induced rapid phosphorylation on tyrosine, serine, and threonine residues and activation of Btk in mouse bone marrowderived mast cells. A small fraction of Btk translocated from the cytosol to the membrane compartment following receptor cross-linking. Tyrosine phosphorylation of Btk was not induced by either a Ca2+ ionophore (A23187), phorbol 12-myristate 13-acetate, or a combination of the two reagents. Coimmunoprecipitation between Btk and receptor subunit i or y was not detected. The data collectively suggest that Btk is not associated with FceRI but that its activation takes place prior to protein kinase C activation and plays a novel role in the FcERI signaling pathway.Cross-linking of the high-affinity immunoglobulin E (IgE) receptor (FccRI) on mast cells and basophils induces a variety of morphological and biochemical changes, culminating in the release of chemical mediators (17). Among early intracellular signaling events, tyrosine phosphorylation of several proteins is thought to be of primary importance (2,4,7,18,21,26,40). Thus, protein-tyrosine kinase (PTK) inhibitors prevent not only tyrosine phosphorylation of cellular proteins but also other early events, including the production of inositol 1,4,5-trisphosphate and histamine release (18). Therefore, PTK activation is thought to be proximal to the activation of phospholipase C (PLC) and protein kinase C (PKC), two enzymes considered essential for mast cell activation.Two subfamilies of PTKs are implicated in this process. The Src family PTKs p56'Y' in RBL-2H3 (a rat basophilic leukemia cell line) and p62cYes in PT-18 (a mouse mast cell line) were found to be associated with FccRI and activated upon receptor cross-linking (8). p60csrc in RBL-2H3 cells was also activated subsequent to receptor cross-linking, although its association with the receptor was not detected. Members of another PTK subfamily, p72"k and PTK72 (which is identical or highly related to p72SYk), were also shown to be activated by FcuRI cross-linking (3, 16). The association of p72syk with the receptor depends on tyrosine phosphorylation of the -y subunit of the receptor (3).In a recent report, some of us described two novel PTK genes expressed in murine mast cells (37). One, termed emb, turned out to be identical to the btk gene, whose mutations in humans a...

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“…Given the fact that many of the candidate anti-inflammatory agents tend to suppress all these cytokines, the action of STE to modulate excessive production of IFN-γ and IL-4 without losing the mitogenic capacity to stimulate IL-2 production should be noted. 16–20…”

Section: Discussionmentioning

confidence: 99%

Regulation of interferon-γ, interleukin-4 and interleukin-2 bySchizonepeta tenuifoliathrough differential effects on nuclear factor-κB, NFATc2 and STAT4/6

Kang

Moon

Sohn

2010

Exp Biol Med (Maywood)

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Contact with antigen on T-cells is made via the T-cell receptor/CD3 complex plus CD28, resulting in the production of cytokines including interleukin (IL)-2, IL-4 and interferon (IFN)-gamma. In particular, dysregulation of IFN-gamma and IL-4 accounts in part for organ-specific autoimmune diseases, allergic inflammation and other chronic inflammatory disorders. The dried above-ground parts of Schizonepeta tenuifolia Briq are used for the treatment of common cold and skin rashes observed in allergic dermatitis, psoriasis and other dermatological disorders in oriental medicine. In the present study, we investigated whether S. tenuifolia water extract (STE) may modulate systemic levels of IFN-gamma, IL-4 and IL-2 in anti-CD3-stimulated mice and the production of those cytokines in anti-CD3-stimulated peripheral blood mononuclear cells (PBMCs). In addition, the effects of STE on anti-CD3-induced activation of several transcription factors were examined. Oral administration of STE significantly reduced the serum levels of IFN-gamma and IL-4 from anti-CD3-treated mice but enhanced those of IL-2. Similar patterns were demonstrated in anti-CD3-stimulated splenocytes and PBMCs in vitro. Further analysis showed that STE enhanced the nuclear translocation of nuclear factor of activated T cells (NFAT)c2 but reduced that of the nuclear factor (NF)-kappaB. The downregulation of IFN-gamma and IL-4 was not mediated by its effects on signal transducer and activator of transcription (STAT)4 and STAT6 activation. These results suggest that the differential regulation of STE on IFN-gamma, IL-4 and IL-2 may be due to its suppression of NF-kappaB, concomitant with its enhancement of NFATc2. Further mechanistic work is required to investigate the role of STE on its modulation of anti-CD3-induced cytokines.

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Differential Inhibition of the T Cell Activation Pathway by Dexamethasone and Cyclosporine

Cited by 14 publications

References 0 publications

A novel mechanism of glucocorticoid-induced immune suppression: the inhibiton of T cell-mediated terminal maturation of a murine dendritic cell line.

A novel mechanism of glucocorticoid-induced immune suppression: the inhibiton of T cell-mediated terminal maturation of a murine dendritic cell line.

Tyrosine phosphorylation and activation of Bruton tyrosine kinase upon Fc epsilon RI cross-linking.

Regulation of interferon-γ, interleukin-4 and interleukin-2 bySchizonepeta tenuifoliathrough differential effects on nuclear factor-κB, NFATc2 and STAT4/6

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