Terfenadine Antagonism Against Interleukin-4-Modulated Gene Expression of T Cell Cytokines

Maeda, Akira; Matsushita, Kiyomi; Yamazaki, Fumie; Kawada, Akira; Tezuka, Tadashi; Aragane, Yoshinori

doi:10.1046/j.1523-1747.2003.12401.x

Cited by 6 publications

(6 citation statements)

References 17 publications

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“…IL-5. The prominent role of AP-1 in IL-4 signaling has previously been shown by our group [4, 20]. Together, this is the first evidence showing that rolipram suppressed IL-4 signaling via functional suppression of AP-1 activation.…”

Section: Discussionsupporting

confidence: 82%

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Antagonism of IL-4 Signaling by a Phosphodiesterase-4 Inhibitor, Rolipram, in Human T Cells

Markova

Niwa

Yamanishi³

et al. 2007

Int Arch Allergy Immunol

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Background: Phosphodiesterase (PDE4) inhibitors prevent breakdown of cAMP and affect the increase in cellular levels of cAMP, which is known to regulate immune cell functions. Because IL-4 plays a causal role in the pathogenesis of allergic disorders, we were interested to study the modulatory mechanisms of a PDE4 inhibitor, rolipram, in IL-4-mediated signaling in T cells. Methods: Human peripheral T cells were stimulated with IL-4 in combination with rolipram, and RT-PCR was performed using primers specific for IL-5. To monitor activation of transcription factors, immunostaining was employed. Results: Rolipram or a cAMP-analogue, 8-Br-cAMP, significantly downregulated IL-4-induced expression of IL-5 mRNA. The rolipram-induced inhibition of IL-5 mRNA was mediated by activation of protein kinase A (PKA), because rolipram-downregulated mRNA expression of IL-5 was restored by PKA inhibitors. Immunostaining revealed that rolipram interfered with IL-4-induced nuclear translocation of activator protein (AP)-1 components. Conclusions: This is the first demonstration of suppression of IL-4 signaling by PDE4 inhibitors via prevention of nuclear translocation of AP-1.

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Section: Discussionsupporting

confidence: 82%

“…We have previously shown that AP-1 is a prominent transcription factor in T cells in response to IL-4 [4, 20]. Therefore, we next checked modulations of AP-1 activation by rolipram.…”

Section: Resultsmentioning

confidence: 99%

Antagonism of IL-4 Signaling by a Phosphodiesterase-4 Inhibitor, Rolipram, in Human T Cells

Markova

Niwa

Yamanishi³

et al. 2007

Int Arch Allergy Immunol

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“…Involvement of the H1-receptor was further ruled out by showing that the inducing effect of TNF-a and TPA, and the inhibitory effect of mizolastine and desloratadine were not significantly modified after overexpression of this receptor. Previous studies with second-generation H1-receptor antagonists have reported that they can diminish DNA binding of NF-kB [17][18][19] or AP-1 [40], but as opposed to the present work, involvement of the H1-receptor was not investigated.…”

Section: Discussionmentioning

confidence: 64%

Histamine H1‐receptor antagonists inhibit nuclear factor‐kappaB and activator protein‐1 activities via H1‐receptor‐dependent and ‐independent mechanisms

Roumestan

Henriquet

Gougat

et al. 2008

Clin Experimental Allergy

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Background Histamine H1-receptor antagonists are used to relieve the symptoms of an immediate allergic reaction. They have additional anti-inflammatory effects that could result from an inhibition of the transcription factors activator protein-1 (AP-1) and nuclear factorkappa B (NF-kB). The implication of the H1-receptor in these effects is controversial. Diphenhydramine is a first-generation H1-receptor antagonist while mizolastine and desloratadine are second-generation compounds. Mizolastine is also an inhibitor of 5-lipoxygenase (5-LO), an enzyme that has been involved in NF-kB activation. Objective We measured the ability of antihistamines to reverse histamine-induced smooth muscle contraction, an effect that involves the H1-receptor. We then investigated whether these drugs affect NF-kB and AP-1 activities in A549 lung epithelial cells, and whether this potential regulation involves H1-receptor and 5-LO. Methods Muscle tone was measured on tracheal segments of guinea-pigs. The H1-receptor was overexpressed by transfection and detected by Western blotting and immunofluorescence microscopy. NF-kB and AP-1 activities were assessed by reporter gene assays in cells overexpressing or not overexpressing the H1-receptor. Production of regulated upon activation, normal T cell expressed andsecreted (RANTES), a chemokine whose expression is induced through NF-kB, was measured using an immunoassay. Results H1-receptor antagonists reversed histamine-induced contraction in a dose-dependent manner. Induction of AP-1 and NF-kB activities by histamine and the down-regulatory effect of antihistamines required overexpression of the H1-receptor. In contrast, when tumour necrosis factor-a and a phorbol ester were used to stimulate NF-kB and AP-1 activities, respectively, repression of these activities did not involve the H1-receptor. Indeed, repression was triggered only by a subset of H1-receptor antagonists and was not stronger after overexpression of the H1-receptor. Mizolastine and desloratadine dose-dependently decreased tumour necrosis factor-a-induced production of RANTES. Diphenhydramine, H2-and H3-receptor antagonists as well as selective inhibitors of 5-LO were ineffective in this assay. Conclusion Repression of NF-kB and AP-1 activities by H1-receptor antagonists involves H1-receptor-dependent and -independent mechanisms but not 5-LO.

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“…It has been shown that some H1‐receptor antagonists inhibit Th2 cytokine production in several experimental conditions [51–53]. Accordingly, application of these drugs may modulate Th1/Th2 cytokine imbalance.…”

Section: Immunomodulatory Effects Of H1‐receptor Antagonistsmentioning

confidence: 99%

Histamine H1-receptor antagonists with immunomodulating activities: potential use for modulating T helper type 1 (Th1)/Th2 cytokine imbalance and inflammatory responses in allergic diseases

Okamoto

Iwata

Ohnuma

et al. 2009

Clinical and Experimental Immunology

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SummaryBeing a first-line treatment for hypersensitivity allergic disease, histamine H1-receptor antagonists possess anti-inflammatory activity in addition to being H1-receptor antagonists. While it is not purely a histamine-related condition, hypersensitivity allergic disease is associated with an increase in the number of T helper type 2 (Th2) cells and Th2 cytokines, and a decrease in the number of Th1 cells and Th1 cytokines. Suppression of Th2-type cytokine production in addition to H1-receptor blockade may therefore represent a successful therapeutic strategy for the treatment of hypersensitivity allergic diseases. H1-receptor antagonists have been reported to modulate immune cascade at various points by acting on T cell-related inflammatory molecules, including adhesion molecules, chemokines and inflammatory cytokines. These effects of H1-receptor antagonists may be optimized for the treatment of allergic diseases. Besides their ability to regulate inflammatory molecules, some H1-receptor antagonists have been reported to downregulate Th2 cytokine production. In particular, it has been shown that several H1-receptor antagonists specifically inhibit the production of Th2, but not Th1, cytokines. Accumulating evidence indicates a crucial role for Th1/Th2 cytokine imbalance on the development of allergic diseases. Accordingly, the use of H1-receptor antagonist with Th2 cytokine inhibitory activity to modulate Th1/Th2 cytokine imbalance might be a favourable strategy for the treatment of hypersensitivity allergic diseases. Furthermore, the identification of H1-receptor antagonists which possess immunoregulatory activities in addition to their anti-histamine activity will provide an important insight into the development of novel immunoregulatory drugs.

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Terfenadine Antagonism Against Interleukin-4-Modulated Gene Expression of T Cell Cytokines

Cited by 6 publications

References 17 publications

Antagonism of IL-4 Signaling by a Phosphodiesterase-4 Inhibitor, Rolipram, in Human T Cells

Antagonism of IL-4 Signaling by a Phosphodiesterase-4 Inhibitor, Rolipram, in Human T Cells

Histamine H1‐receptor antagonists inhibit nuclear factor‐kappaB and activator protein‐1 activities via H1‐receptor‐dependent and ‐independent mechanisms

Histamine H1-receptor antagonists with immunomodulating activities: potential use for modulating T helper type 1 (Th1)/Th2 cytokine imbalance and inflammatory responses in allergic diseases

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