Th17-Associated Cytokines as a Therapeutic Target for Steroid-Insensitive Asthma

Morishima, Yuko; Ano, Satoshi; Ishii, Yukio; Ohtsuka, Shigeo; Matsuyama, Masashi; Kawaguchi, Mio; Hizawa, Nobuyuki

doi:10.1155/2013/609395

Cited by 52 publications

(39 citation statements)

References 95 publications

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“…Our results demonstrating low sensitivity of Th 17 cells, both in vivo and in vitro, to the inhibitory action of MP (13,14.19) have been later confirmed by findings that T lymphocytes derived from MS patients with an enhanced Th17-like phenotype are less sensitive to hydrocortisone inhibition (23) and severe forms of allergic asthma associated with Th17 response are poorly controlled by corticosteroids (24). Moreover, it has been recently shown that not only Th17 cells are refractory to the inhibitory actions of steroids but also that these cells are actively and specifically selected for within mixed T cell cultures upon exposure to steroids (25).…”

Section: Resultssupporting

confidence: 68%

Different response to glucocorticoid therapy in autoimmune diseases of CNS

Stanojević¹,

Mostarica-Stojković²

2016

Medicinski podmladak

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SažetakTh17 ćelije i njihov glavni citokin interleukin 17 (IL-17), imaju ulogu u patogenezi autoimunskih oboljenja centralnog nervnog sistema kao što su multipla skleroza i eksperimentalni autoimunski encefalomijelitis (EAE). Efekat glukokortikoida (GK), lekova koji se primenjuju kao terapija inflamatornih i autoimunskih oboljenja, na ekspresiju i proizvodnju IL-17, još uvek nije detaljno ispitan. Nije precizno definisano ni mesto dejstva GK. U ovom radu su prikazani glavni rezultati doktorske disertacije posvećene ispitivanju dejstva GK na proizvodnju IL-17 na modelu EAE indukovanog kod pacova, koji su povezani sa najnovijim saznanjima o efektima GK na Th17 ćelije kod ljudi i na animalnim modelima. Metilprednizolon (MP), sintetski glukokortikoid, inhibira in vitro proizvodnju IL-17 od strane ćelija limfnog čvora pacova stimulisanih mitogenom i antigenom na dozno zavisan način. Pod istim uslovima je značajno više izraženo inhibitorno delovanje MP na proizvodnju i ekspresiju gena za interferon gama (IFN-γ), citokina koji stvaraju Th1 ćelije. Isti obrazac delovanja MP na ekspresiju i proizvodnju IL-17 i IFN-γ zapažen je i na ćelijama izolovanim iz kičmene moždine pacova obolelih od EAE, čime je takođe pokazano da MP ostvaruje svoje efekte ne samo u perifernom limfnom tkivu, već i u ciljanom tkivu. Različita osetljivost Th1 i Th17 limfocita koji su glavni ćelijski izvori IFN-γ, odnosno IL-17 na delovanje GK zapažena je na drugim animalnim modelima i u bolestima kod ljudi. Razumevanje molekulskih mehanizama koji leže u osnovi relativne otpornosti Th17 ćelija na delovanje GK od ključnog je značaja za razvoj novih strategija u lečenju onih oblika autoimunskih i hroničnih bolesti koje su rezistentne na delovanje glukokortikoida.Ključne reči: autoimunost, eksperimentalni autoimunski encefalomijelitis, metilprednizolon, IL-17, Th17 Abstract Th17 cells and interleukin (IL-17), their signature cytokine, have the main role in the pathogenesis of autoimmune diseases of the central nervous system such as multiple sclerosis and experimental autoimmune encephalomyelitis (EAE). The effect of glucocorticoids (GC) on expression and production of IL-17 has not been thoroughly tested yet. Also, the site of action of GC is not precisely defined. This paper presents the main results of the Doctoral thesis devoted to studies of GC on the production of IL-17 in the model of EAE, induced in susceptible laboratory animals. Methylprednisolone (MP), a synthetic glucocorticoid, inhibit in vitro production of IL-17 in mitogen-stimulated lymph node cells (LNC) as well as in myelin basic protein (MBP)-stimulated draining LNC in dose-dependent manner. However, under the same conditions inhibitory effect of the MP on production and expression of the genes for IFN-γ, a cytokine that TH1 cells generate, is significantly more pronounced. Interestingly, when we analyzed effects of MP applied in vivo in EAE, the same phenomenon was observed: the proportion of IFN-γ producing, but not all of IL-17 cells were reduced in cells isolated from MP treated ra...

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Section: Resultssupporting

confidence: 68%

Different response to glucocorticoid therapy in autoimmune diseases of CNS

Stanojević¹,

Mostarica-Stojković²

2016

Medicinski podmladak

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“…There has been an increase in the literature of evidence supporting a role of the IL-17/neutrophil axis in more severe and glucocorticoid-resistant subsets of patients (1, 3, 30, 31). We report here that human primary Th17 cells and mouse in vitro differentiated Th17 cells do not undergo glucocorticoid-induced apoptosis.…”

Section: Discussionmentioning

confidence: 99%

BCL-2 protects human and mouse Th17 cells from glucocorticoid-induced apoptosis

Banuelos

Shin

Cao

et al. 2016

Allergy

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Background Glucocorticoid resistance has been associated with Th17-driven inflammation, the mechanisms of which are not clear. We determined whether human and mouse Th17 cells are resistant to glucocorticoid-induced apoptosis. Methods Freshly isolated human blood Th17 cells and in vitro differentiated Th17 cells from IL-17F red fluorescent protein reporter mice were treated with dexamethasone, a potent glucocorticoid. Apoptosis was measured using annexin V and DAPI staining. Screening of apoptosis genes was performed using the apoptosis PCR array. Levels of molecules involved in apoptosis were measured using quantitative RT-PCR, flow cytometry, and Western blotting. Knockdown of BCL-2 in murine Th17 cells was performed via retroviral transduction. Cytokines were measured using ELISA. A murine Th17-driven severe asthma model was examined for Th17 glucocorticoid sensitivity in vivo. Results Human and mouse Th17 cells and mouse Th2 cells were resistant to glucocorticoid-induced apoptosis. Th17 cells had glucocorticoid receptors levels comparable to those in other T effectors cells. Th17 cells had high levels of BCL-2, knockdown of which sensitized Th17 cells to dexamethasone-induced apoptosis. Production of IL-22, but not IL-17A and IL-17F, was suppressed by glucocorticoids. STAT3 phosphorylation in Th17 cells was insensitive to glucocorticoid inhibition. Lung Th17 cells in the murine severe asthma model were enhanced, rather than suppressed, by glucocorticoids. Conclusion Th17 cells are resistant to glucocorticoid-induced apoptosis and cytokine suppression, at least in part due to high levels of BCL-2. These findings support a role of Th17 cells in glucocorticoid-resistant inflammatory conditions such as certain endotypes of asthma.

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“…From this perspective, a special focus on screening of treatments that not only control symptoms of asthma, but also modify T cell function is recommended. Various lines of evidence indicate that T helper 17 (Th17) is a third distinct lineage of CD4 þ T cells independent of Th1 and Th2 cell types with its signature cytokine IL-17A, and have crucial role in asthma pathogenesis (Durrant and Metzger, 2010;Stelmaszczyk-Emmel et al, 2013) and were considered to be closely associated with refractory asthma (Cosmi et al, 2011;Morishima et al, 2013). Regulatory T (Treg) cells is another subtype of CD4 þ T cells with general immunosuppressive effect, and played considerable role in controlling allergic diseases such as asthma (Ray et al, 2010).…”

Section: Introductionmentioning

confidence: 99%