Topical suplatast tosilate (IPD) ameliorates Th2 cytokine-mediated dermatitis in caspase-1 transgenic mice by downregulating interleukin-4 and interleukin-5

Murakami, Takaaki; Yamanaka, Keiichi; Tokime, Kazuya; Kurokawa, Ichiro; Tsutsui, Hiroko; Nakanishi, Kenji; Mizutani, Hitoshi

doi:10.1111/j.1365-2133.2006.07241.x

Cited by 20 publications

(10 citation statements)

References 26 publications

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“…This finding is partly in accordance with an observation by Matsui et al, [35], who reported that PBMC from suplatast tosilate responders with childhood asthma produced higher amounts of IFN-than those of suplatast tosilate non-responders. The findings are also more directly in accordance with those by Murakami et al, [36], who found that suplatast tosilate treatment significantly suppressed the elevated expression of IL-4, IL-5, and IFN-mRNA in caspase-1 transgenic mice that spontaneously developed ADlike dermatitis. They also observed that suplatast tosilate treatment significantly decreased the expression of IL-18, which induced Th1 responses in synergy with IL-12, possibly explaining the mechanism of suplatast tosilate efficacy for Th1-related responses.…”

Section: Il-4/il-12 Snps and Efficacy Of Suplatast Tosilate In Atopicsupporting

confidence: 92%

IL-4 and IL-12 Polymorphisms are Associated with Response to Suplatast Tosilate, a Th2 Cytokine Inhibitor, in Patients with Atopic Dermatitis

Nagase

Nakachi

Ishida

et al. 2012

TODJ

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Th2-related immune and inflammatory responses have been implicated in the pathogenesis of atopic dermatitis (AD), but few clinical lines of evidence have been reported regarding how and whether Th2-related responses are associated with other risk factors in the treatment of AD patients. In this study, the associations between the polymorphisms of genes related to the pathophysiology of AD and the efficacy of suplatast tosilate, an oral immunemodulator known to downregulate Th2-related allergic responses, were analyzed in adult patients with chronic AD. Patients were recruited from our previous study, where suplatast tosilate was evaluated for its efficacy when used in combination with topical steroids. The genotypes of 35 single nucleotide polymorphisms (SNPs) of 27 genes related to AD pathogenesis were then determined in 17 responders and 18 non-responders, as defined by the improvement rate in their AD skin scores. While no significant difference in the patient background was observed between responders and non-responders, significant associations were noted between the response to treatment with suplatast tosilate and three SNPs of IL-4 (-590C/T: P=0.04, -33C/T: P=0.04) and IL-12B (1188A/C: P=0.03), but not for the other SNPs. Of note, ethnic differences in the genotype frequencies of IL-4 -590C/T and IL-12B 1188A/C SNPs were found. In conclusion, the present results raise the possibility that AD patients who tend to produce more IL-4 and IL-12 may be susceptible to suplatast tosilate treatment and that ethnic variations should be considered to further understand the role of Th2-related responses.

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Section: Il-4/il-12 Snps and Efficacy Of Suplatast Tosilate In Atopicsupporting

confidence: 92%

IL-4 and IL-12 Polymorphisms are Associated with Response to Suplatast Tosilate, a Th2 Cytokine Inhibitor, in Patients with Atopic Dermatitis

Nagase

Nakachi

Ishida

et al. 2012

TODJ

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“…Suplatast tosilate (IPD-1151T) is an immunomodulator that suppresses eosinophil infiltration, IgE production, and allergic inflammation by suppressing the production of IL-4 and IL-5 (25). The efficacy of systemic administration of suplatast in nasal allergy has been reported (26).…”

Section: A Llergic Rhinitis (Ar)mentioning

confidence: 99%

Suplatast Tosilate Inhibits Histamine Signaling by Direct and Indirect Down-Regulation of Histamine H1 Receptor Gene Expression through Suppression of Histidine Decarboxylase and IL-4 Gene Transcriptions

Shahriar

Mizuguchi

Maeyama

et al. 2009

The Journal of Immunology

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Allergic rhinitis (AR) is an inflammatory disorder typified by symptoms such as sneezing, congestion, and rhinorrhea. Histamine plays important roles in eliciting AR symptoms. Up-regulation of the histamine H1 receptor (H1R) and histidine decarboxylase (HDC) mRNAs was observed in AR patients. Th2 cytokines are also involved in the pathogenesis of AR. We examined the effect of suplatast tosilate on nasal symptoms, and H1R, HDC, and IL-4 gene expression using toluene-2,4-diisocyanate (TDI)-sensitized rats and HeLa cells expressing endogenous H1R. Provocation with TDI increased nasal symptoms, HDC activity, the histamine content of nasal lavage fluid, and the expression of H1R, HDC, and IL-4 mRNAs in TDI-sensitized rats. Pretreatment with suplatast for 2 wk significantly suppressed TDI-induced nasal symptoms and elevation of H1R, HDC, and IL-4 mRNAs. Suplatast also suppressed HDC activity in the nasal mucosa and the histamine content of the nasal lavage fluid. Bilateral injection of IL-4 into the nasal cavity of normal rats up-regulated H1R mRNA, while intranasal application of histamine up-regulated IL-4 mRNA. Suplatast suppressed IL-4-induced up-regulation of H1R mRNA in HeLa cells. However, it did not inhibit histamine-induced H1R mRNA elevation. These results suggest that suplatast alleviates nasal symptoms by inhibiting histamine signaling in TDI-sensitized rats through the suppression of histamine- and IL-4-induced H1R gene expression by the inhibitions of HDC and IL-4 gene transcriptions, respectively.

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“…Pro‐IL‐1β maturation was shown to be dependent on caspase‐1 enzymatic activity, whereas NF‐κB activation was found to be independent of caspase‐1 activity (14). In addition, the serum level of IL‐18 was previously shown to be increased in caspase‐1 transgenic mouse (27). Likewise, our results showed that kanamycin increased the enzymatic activity of caspase‐1 as well as the mRNA expression and production of IL‐1β and IL‐18.…”

Section: Discussionmentioning

confidence: 93%

“…Serum IgE and histamine levels from a murine model of asthma were increased (26). In caspase‐1 transgenic mice, histamine and IgE were increased in the serum (27). In our study, when caspase‐1 activity was increased by kanamycin, the histamine and IgE level were also increased.…”

Section: Discussionmentioning

confidence: 99%

Kanamycin activates caspase-1 in NC/Nga mice

Han

Kim

Jeong

2011

Experimental Dermatology

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Abuse of antibiotics to treat children has been associated with an increased risk of the development of inflammatory diseases. The underlying mechanism behind this association still remains to be clarified. Here, we examined the mechanisms behind kanamycin‐induced skin inflammation in NC/Nga mice. NC/Nga mice were orally administered kanamycin for 7 days consecutively. Blood, spleen and dorsal skin were taken 18 weeks after kanamycin treatment was stopped. Kanamycin significantly increased the allergic reaction. We also observed significant increases in caspase‐1 mRNA and protein expression in the dorsal skin of the kanamycin‐administered mice compared to the control mice. The increased enzymatic activity of caspase‐1 in the dorsal skin of the kanamycin‐administered mice increased the mRNA expressions of IL‐1β and IL‐18. The productions of IL‐1β and IL‐18 were also increased in the splenocytes obtained from kanamycin‐administered mice. Kanamycin upregulated the TNF‐α mRNA expression in the dorsal skin and the TNF‐α production in stimulated splenocytes. The activation of nuclear factor‐κB and degradation of IκBα were increased by kanamycin administration. Our findings suggest that the use of kanamycin during infancy may increase the potential for skin inflammatory reactions through the upregulation of caspase‐1.

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Topical suplatast tosilate (IPD) ameliorates Th2 cytokine-mediated dermatitis in caspase-1 transgenic mice by downregulating interleukin-4 and interleukin-5

Abstract: This study shows that topical therapy with IPD inhibits the expression of IL-4 and IL-5 and ameliorates skin manifestations in an AD mouse model, suggesting the potential usefulness of topical IPD for the treatment of AD.

Cited by 20 publications

References 26 publications

IL-4 and IL-12 Polymorphisms are Associated with Response to Suplatast Tosilate, a Th2 Cytokine Inhibitor, in Patients with Atopic Dermatitis

IL-4 and IL-12 Polymorphisms are Associated with Response to Suplatast Tosilate, a Th2 Cytokine Inhibitor, in Patients with Atopic Dermatitis

Suplatast Tosilate Inhibits Histamine Signaling by Direct and Indirect Down-Regulation of Histamine H1 Receptor Gene Expression through Suppression of Histidine Decarboxylase and IL-4 Gene Transcriptions

Kanamycin activates caspase-1 in NC/Nga mice

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