Cigarette Smoke Extract Enhances IL-17A-Induced IL-8 Production via Up-Regulation of IL-17R in Human Bronchial Epithelial Cells

Lee, Kyoung-Hee,Lee, Chang-Hoon,Woo, Jisu,Jeong, Jiyeong,Jang, An-Hee,Yoo, Chul-Gyu Korean Society for Molecular and Cellular Biology 2018 Molecules and cells Vol.41 No.4

Interleukin-17A (IL-17A) is a pro-inflammatory cytokine mainly derived from T helper 17 cells and is known to be involved in the pathogenesis of chronic obstructive pulmonary disease (COPD). Cigarette smoke (CS) has been considered as a primary risk factor of COPD. However, the interaction between CS and IL-17A and the underlying molecular mechanisms have not been clarified. In the current study, we investigated the effects of cigarette smoke extract (CSE) on IL-17A-induced IL-8 production in human bronchial epithelial cells, and sought to identify the underlying molecular mechanisms. IL-8 production was significantly enhanced following treatment with both IL-17A and CSE, while treatment with either IL-17A or CSE alone caused only a slight increase in IL-8 production. CSE increased the transcription of IL-17RA/RC and surface membrane expression of IL-17R, which was suppressed by an inhibitor of the phosphoinositide 3-kinase (PI3K)/Akt pathway (LY294002). CSE caused inactivation of glycogen synthase $kinase-3{\beta}$ ($GSK-3{\beta}$) via the PI3K/Akt pathway. Blockade of $GSK-3{\beta}$ inactivation by overexpression of constitutively active $GSK-3{\beta}$ (S9A) completely suppressed the CSE-induced up-regulation of IL-17R expression and the CSE-induced enhancement of IL-8 secretion. In conclusion, inactivation of $GSK-3{\beta}$ via the PI3K/Akt pathway mediates CSE-induced up-regulation of IL-17R, which contributes to the enhancement of IL-17A-induced IL-8 production.

Cigarette Smoke Extract Enhances IL-17A-Induced IL-8 Production via Up-Regulation of IL-17R in Human Bronchial Epithelial Cells

이경희,이창훈,우지수,정지영,장안희,유철규 한국분자세포생물학회 2018 Molecules and cells Vol.41 No.4

Interleukin-17A (IL-17A) is a pro-inflammatory cytokine mainly derived from T helper 17 cells and is known to be involved in the pathogenesis of chronic obstructive pulmonary disease (COPD). Cigarette smoke (CS) has been considered as a primary risk factor of COPD. However, the interaction between CS and IL-17A and the underlying molecular mechanisms have not been clarified. In the current study, we investigated the effects of cigarette smoke extract (CSE) on IL-17A-induced IL-8 production in human bronchial epithelial cells, and sought to identify the underlying molecular mechanisms. IL-8 production was significantly enhanced following treatment with both IL-17A and CSE, while treatment with either IL-17A or CSE alone caused only a slight increase in IL-8 production. CSE increased the transcription of IL-17RA/RC and surface membrane expression of IL-17R, which was suppressed by an inhibitor of the phosphoinositide 3-kinase (PI3K)/Akt pathway (LY294002). CSE caused inactivation of glycogen synthase kinase-3β (GSK-3β) via the PI3K/Akt pathway. Blockade of GSK-3β inactivation by overexpression of constitutively active GSK-3β (S9A) completely suppressed the CSE-induced up-regulation of IL-17R expression and the CSE-induced enhancement of IL-8 secretion. In conclusion, inactivation of GSK-3β via the PI3K/Akt pathway mediates CSE-induced up-regulation of IL-17R, which contributes to the enhancement of IL-17A-induced IL-8 production.

흰쥐 가슴샘 재생과정에서 IL-17A의 발현 특성

최학종(Hak-Jong Choi),이희우(Hee-Woo Lee),박종훈(Jong-Hun Park),오세옥(Sae-Ock Oh),백선용(Sun-Yong Baek),김봉선(Bong-Seon Kim),윤식(Sik Yoon) 대한체질인류학회 2011 해부·생물인류학 (Anat Biol Anthropol) Vol.24 No.3

IL-17A는 활성화된 T 세포에 의해 분비되는 사이토카인으로 5개의 연관된 사이토카인인 IL-17B, IL-17C, IL-17D, IL-17E 및 IL-17F과 함께 IL-17 family로 분류되며, 이들은 모두 유사한 단백질 구조를 가지고 있다. IL-17A와 IL-17F는 활성화된 T 세포에서 발현되는 반면 IL-17B, IL-17C, IL-17D 및 IL-17E는 모든 조직에서 광범위하게 발현되며 이들의 기능은 IL-17A와 부분적으로 일치하지만 이에 관해서 자세히 연구되어 있지 않다. 가슴샘버팀질세포는 가슴샘세포의 증식, 성숙 및 분화의 조절에 중요한 역할을 하는 것으로 알려져 있기 때문에, 본 연구에서는 가슴샘세포, 가슴샘상피세포, 큰포식세포, 가슴샘가지돌기세포 및 가슴샘종양세포에서 역전사 중합효소 연쇄반응법을 이용하여 IL-17 family의 발현 특성을 확인하였다. 또한 cyclophosphamide를 흰쥐에 투여하여 가슴샘의 급성 퇴축을 유발시킨 다음 3, 7 및 14일째 실험 동물을 희생시켜, 가슴샘 재생과정 동안 시간의 경과에 따른 IL-17 family와 IL-17 수용체(IL-17R)의 발현특성을 역전사 중합효소 연쇄반응법을 통해 조사하였으며, IL-17A의 경우는 면역조직화학법을 이용하여 그 발현양상을 더 구체적으로 분석하였다. 그 결과 IL-17A와 IL-17E는 가슴샘종양세포에서만 발현되었고 IL-17C는 큰포식세포를 제외한 모든 세포에서 발현되고 있음을 확인하였다. IL-17F의 경우 실험군의 모든 세포에서 발현된 반면에 IL-17B와 IL-17D는 전혀 발현되지 않았다. 또한 IL-17A는 가슴샘 재생과정 중 가슴샘세포와 가슴샘버팀질세포에서 모두 증가되었으며 IL-17A의 수용체인 IL-17R은 재생모델의 가슴샘세포와 가슴샘버팀질세포에서 발현양이 거의 유사하였다. 면역조직화학법을 이용한 분석에서도 재생과정 동안 상피세포에서 IL-17A의 발현이 증가됨을 확인하였다. 따라서 가슴샘세포와 가슴샘 상피세포에서 IL-17A의 발현 및 그 수용체를 통한 신호전달은 가슴샘의 급성퇴축 이후 가슴샘이 재생되는 과정에 중요한 역할을 할 것으로 생각된다. IL-17A is a pro-inflammatroy cytokine secreted by activated T cells. The IL-17 family consist of IL-17A, IL-17B, IL-17C, IL-17D, IL-17E and IL-17F. IL-17A and IL-17F are produced primarily in activated T cells. In contrast, IL-17B, IL-17C, IL-17D and IL-17E are expressed in a wide assortment of tissues. Their functions partially overlap those of IL-17A, although they have not been as thoroughly investigated. The receptor for IL-17A (IL-17R) is widely expressed in a variety of tissues. IL-17A and IL-17E mRNAs were expressed in only EL4 cells. IL-17C mRNA expression was observed in the thymic subcapsular/cortex epithelial cells (SNEC), cortex or cortical reticular cells (CREC), medullary epithelial cells (MEC), medullary interdigitating-like cells (MDC), thymocytes and EL4 cells. However, IL-17C mRNA was not expressed in RAW 264.7 cells. Immunohistochemical study also demonstrated not only the presence of IL-17A mainly in the thymic epithelial cells, but also the upregulated expression of IL-17A in the thymic epithelial cells of the regenerating thymus. Thus, the results of the present study suggest that IL-17A expressed in the thymocytes and thymic epithelial cells could play an important role in the development of new T cells to replace T cells damaged by cyclophosphamide treatment during thymus regeneration.

Early IL-17A Prevention Rather Than Late IL-17A Neutralization Attenuates Toluene Diisocyanate-Induced Mixed Granulocytic Asthma

Chen Shuyu,Yu Li,Deng Yao,Liu Yuanyuan,Wang Lingwei,Li Difei,Yang Kai,Liu Shengming,Tao Ailin,Chen Rongchang 대한천식알레르기학회 2022 Allergy, Asthma & Immunology Research Vol.14 No.5

Purpose: Interleukin (IL)-17A plays a critical role in the pathogenesis of allergic airway inflammation. Yet, the exact roles of IL-17A in asthma are still controversial. Thus, the aim of this study was to dissect the roles of IL-17A in toluene diisocyanate (TDI)-induced mixed granulocytic asthma and to assess the effects of neutralizing antibody in different effector phases on TDI-induced asthma. Methods: IL-17A functions in allergic airway inflammation were evaluated using mice deficient in IL-17A (Il17a−/−) or IL-17A monoclonal antibody (IL-17A mab, intraperitoneally, 50 μg per mouse, 100 μg per mouse). Moreover, the effects of exogenous recombinant IL (rIL)-17A in vivo (murine rIL-17A, intranasally, 1 μg per mouse) and in vitro (human rIL-17A, 100 ng/mL) were investigated. Results: TDI-induced mixed granulocytic airway inflammation was IL-17A-dependent because airway hyperreactivity, neutrophil and eosinophil infiltration, airway smooth muscle thickness, epithelium injury, dysfunctional T helper (Th) 2 and Th17 responses, granulocytic chemokine production and mucus overproduction were more markedly reduced in the Il17a−/− mice or by IL-17A neutralization during the sensitization phase of wild-type (WT) mice. By contrast, IL-17A neutralization during the antigen-challenge phase aggravated TDI-induced eosinophils recruitment, with markedly elevated Th2 response. In line with this, instillation of rIL-17 during antigen sensitization exacerbated airway inflammation by promoting neutrophils aggregation, while rIL-17A during the antigen-challenge phase protected the mice from TDI-induced airway eosinophilia. Moreover, rIL-17A exerted distinct effects on eosinophil- or neutrophil-related signatures in vitro. Conclusions: Our data demonstrated that IL-17A was required for the initiation of TDI-induced asthma, but functioned as a negative regulator of established allergic inflammation, suggesting that early abrogation of IL-17A signaling, but not late IL-17A neutralization, may prevent the progression of TDI-induced asthma and could be used as a therapeutic strategy for severe asthmatics in clinical settings.

Role of IL-17A in Chronic Rhinosinusitis With Nasal Polyp

Gwanghui Ryu,Jun-Sang Bae,Jihye Kim,Eun Hee Kim,Lele Lyu,Young-Jun Chung,모지훈 대한천식알레르기학회 2020 Allergy, Asthma & Immunology Research Vol.12 No.3

Purpose: Th17-associated inflammation is increased in chronic rhinosinusitis with nasal polyp (CRSwNP), and is associated with disease severity and steroid resistance. Overexpressed interleukin (IL)-17A affects CRSwNP by tissue remodeling, eosinophilic accumulation, and neutrophilic infiltration. We aimed to identify the role of IL-17A in CRSwNP and to evaluate the effects of anti-IL-17A blocking antibody on nasal polyp (NP) formation using a murine NP model. Moreover, we sought to investigate whether the inhibition of mechanistic target of the rapamycin (mTOR) signal pathway could suppress IL-17A expression and NP formation. Methods: Human sinonasal tissues from control subjects and patients with chronic rhinosinusitis (CRS) were analyzed using immunohistochemistry (IHC) and immunofluorescence staining. The effects of IL-17A neutralizing antibody and rapamycin were evaluated in a murine NP model. Mouse samples were analyzed using IHC, quantitative real-time polymerase chain reaction, and enzyme-linked immunosorbent assay. Results: IL-17A+ inflammatory cells were significantly increased in number in NP from patients with CRSwNP compared to that in uncinate process tissues from control subjects and patients with CRS without NP or CRSwNP. CD68+ M1 macrophages dominantly expressed IL-17A, followed by neutrophils and T helper cells, in NP tissues. Neutralization of IL-17A effectively reduced the number of NPs, inflammatory cytokines, and IL-17A-producing cells, including M1 macrophages. Inhibition of IL-17A via the mTOR pathway using rapamycin also attenuated NP formation and inflammation in the murine NP model. Conclusions: IL-17A possibly plays a role in the pathogenesis of CRSwNP, the major cellular source being M1 macrophage in NP tissues. Targeting IL-17A directly or indirectly may be an effective therapeutic strategy for CRSwNP.

Association between Polymorphisms of Interleukin-17A and Interleukin-17F Genes and Silicosis Susceptibility in Chinese Han People

Chen, Ying,Fan, Xue-Yun,Jin, Yu-Lan,Yao, San-Qiao,Yun, Xiang,Hua, Zheng-Bing,Shen, Fu-Hai Asian Pacific Journal of Cancer Prevention 2014 Asian Pacific journal of cancer prevention Vol.15 No.20

Background: To explore the relationship between polymorphisms of interleukin17 (IL-17) gene(A-832G 7488A/G) and the susceptibility to silicosis, a risk factor for lung cancer. Materials and Methods: A total of 113 silicosis patients and 116 workers without silicosis were enrolled in the case-control study. IL-17A A-832G and IL-17F 7488A/G polymorphisms were evaluated by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Results: The frequencies of AA,GG and AG of IL-17A A-832G locus in the case and control groups were 46.9%, 8.0%, 45.1%, and 49.2%, 7.6%, 43.2%, respectively, with no significant differences (p>0.05).The GG genotype in the IL-17F (7488A/G) locus was not found. The frequencies of AA and GA of IL-17F 7488A/G locus in the case and control groups were 84.1%, 15.9% and 66.4%, 33.6%, respectively (p<0.05). Analysis of combined effects showed that the individuals with GG+AG genotype of IL-17A and GG+GA genotype of IL-17F are protected against silicosis (OR=0.469). Conclusions: IL-17F 7488A/G is associated with susceptibility to silicosis, and G allele may have a protective effect. No relationship was found between IL-17A gene polymorphisms at A-832G and silicosis.

Elevated Serum IL-17A but not IL-6 in Glioma Versus Meningioma and Schwannoma

Doroudchi, Mehrnoosh,Pishe, Zahra Ghanaat,Malekzadeh, Mahyar,Golmoghaddam, Hossein,Taghipour, Mousa,Ghaderi, Abbas Asian Pacific Journal of Cancer Prevention 2013 Asian Pacific journal of cancer prevention Vol.14 No.9

Background: There is a Th1/Th2 cytokine imbalance and expression of IL-17 in patients with brain tumours. We aimed to compare the levels of IL-17A and IL-6 in sera of glioma, meningioma and schwannoma patients as well as in healthy individuals. Materials and Methods: IL-17A and IL-6 levels were measured in sera of 38 glioma, 24 meningioma and 18 schwannoma patients for comparison with 26 healthy controls by commercial ELISA assays. Results: We observed an increase in the IL-17A in 30% of glioma patients while only 4% and 5.5% of meningioma and schwannoma patients and none of the healthy controls showed elevated IL-17A in their sera ($0.29{\pm}0.54$, $0.03{\pm}0.15$ and $0.16{\pm}0.68$ vs. $0.00{\pm}0.00pg/ml$; p=0.01, p=0.01 and p=0.001, respectively). There was also a significant decrease in the level of IL-6 in glioma patients compared to healthy controls ($2.34{\pm}4.35$ vs. $4.67{\pm}4.32pg/ml$; p=0.01). There was a direct correlation between the level of IL-17A and age in glioma patients (p=0.005). Glioma patients over 30 years of age had higher IL-17A and lower IL-6 in their sera compared to the young patients. In addition, a non-significant grade-specific inverse trend between IL-17A and IL-6 was observed in glioma patients, where high-grade gliomas had higher IL-17A and lower IL-6. Conclusions: Our data suggest a Th17 mediated inflammatory response in the pathogenesis of glioma. Moreover, tuning of IL-6 and IL-17A inflammatory cytokines occurs during progression of glioma. IL-17A may be a potential biomarker and/or immunotherapeutic target in glioma cases.

IL-17A and Th17 Cells Contribute to Endometrial Cell Survival by Inhibiting Apoptosis and NK Cell Mediated Cytotoxicity of Endometrial Cells via ERK1/2 Pathway

Kang Young-Ju,Cho Hee Jun,Lee Yunhee,Park Arum,Kim Mi Jeong,Jeung In Cheul,Jung Yong-Wook,Jung Haiyoung,Choi Inpyo,Lee Hee Gu,Yoon Suk Ran 대한면역학회 2023 Immune Network Vol.23 No.2

Immune status including the immune cells and cytokine profiles has been implicated in the development of endometriosis. In this study, we analyzed Th17 cells and IL-17A in peritoneal fluid (PF) and endometrial tissues of patients with (n=10) and without (n=26) endometriosis. Our study has shown increased Th17 cell population and IL-17A level in PF with endometriosis patients. To determine the roles of IL-17A and Th17 cells in the development of endometriosis, the effect of IL-17A, major cytokine of Th17, on endometrial cells isolated from endometriotic tissues was examined. Recombinant IL-17A promoted survival of endometrial cells accompanied by increased expression of anti-apoptotic genes, including Bcl-2 and MCL1, and the activation of ERK1/2 signaling. In addition, treatment of IL-17A to endometrial cells inhibited NK cell mediated cytotoxicity and induced HLA-G expression on endometrial cells. IL-17A also promoted migration of endometrial cells. Our data suggest that Th17 cells and IL-17A play critical roles in the development of endometriosis by promoting endometrial cell survival and conferring a resistance to NK cell cytotoxicity through the activation of ERK1/2 signaling. Targeting IL-17A has potential as a new strategy for the treatment of endometriosis.

IL-17A induces osteoblast differentiation by activating JAK2/STAT3 in ankylosing spondylitis

Jo, Sungsin,Wang, Sung Eun,Lee, Young Lim,Kang, Suman,Lee, Bitnara,Han, Jinil,Sung, Il-Hoon,Park, Ye-Soo,Bae, Sang-Cheol,Kim, Tae-Hwan BioMed Central 2018 Arthritis research & therapy Vol.20 No.-

<P><B>Background</B></P><P>IL-17A has recently emerged as a potential target that regulates the extensive inflammation and abnormal bone formation observed in ankylosing spondylitis (AS). Blocking IL-17A is expected to inhibit bony ankylosis. Here, we investigated the effects of anti IL-17A agents in AS.</P><P><B>Methods</B></P><P>TNFα, IL-17A, and IL-12/23 p40 levels in serum and synovial fluid from patients with ankylosing spondylitis (AS), rheumatoid arthritis (RA), osteoarthritis (OA), or healthy controls (HC) were measured by ELISA. Bone tissue samples were obtained at surgery from the facet joints of ten patients with AS and ten control (Ct) patients with noninflammatory spinal disease. The functional relevance of IL-17A, biological blockades, Janus kinase 2 (JAK2), and non-receptor tyrosine kinase was assessed in vitro with primary bone-derived cells (BdCs) and serum from patients with AS.</P><P><B>Results</B></P><P>Basal levels of IL-17A and IL-12/23 p40 in body fluids were elevated in patients with AS. JAK2 was also highly expressed in bone tissue and primary BdCs from patients with AS. Furthermore, addition of exogenous IL-17A to primary Ct-BdCs promoted the osteogenic stimulus-induced increase in ALP activity and mineralization. Intriguingly, blocking IL-17A with serum from patients with AS attenuated ALP activity and mineralization in both Ct and AS-BdCs by inhibiting JAK2 phosphorylation and downregulating osteoblast-involved genes. Moreover, JAK2 inhibitors effectively reduced JAK2-driven ALP activity and JAK2-mediated events.</P><P><B>Conclusions</B></P><P>Our findings indicate that IL-17A regulates osteoblast activity and differentiation via JAK2/STAT3 signaling. They shed light on AS pathogenesis and suggest new rational therapies for clinical AS ankylosis.</P><P><B>Electronic supplementary material</B></P><P>The online version of this article (10.1186/s13075-018-1582-3) contains supplementary material, which is available to authorized users.</P>

Characteristic clinical features of Korean atopic dermatitis patients with IL-17 receptor a mutation

( Jong Won Lee ),( Kwangmin Yu ),( Hyeyoung Lee ),( Eung Ho Choi ) 대한피부과학회 2020 대한피부과학회 학술발표대회집 Vol.72 No.1

Background: Cytokines including interleukin-17A (IL-17A) contribute to the pathogenesis of atopic dermatitis (AD). IL-17A binds to heterodimeric receptor composed of IL-17 receptor A (IL-17RA) and IL-17 receptor C (IL-17RC), and acts to promote the recruitment of neutrophils and induce the production of antimicrobial peptides. Dysregulation of the IL-17A/IL-17RA axis is implicated in inflammatory skin diseases. Objectives: This study aimed to characterize the clinical features of AD according to the presence of IL-17RA mutation in Korean AD patients. Methods: We performed the reverse blot hybridization assay to detect IL-17RA mutation in Korean patients with AD. The clinical features of AD were compared between the patients of AD with and without IL-17RA mutation. Results: Among a total of 344 AD patients, 27 patients (7.85%) were found to have IL-17RA mutation. All AD patients with IL-17RA mutation had extrinsic type AD. In addition, AD with IL-17RA mutation was associated with longer disease duration, higher blood eosinophil count, higher serum IgE level and higher house dust mite allergen specific IgE levels. Conclusion: In Korean patients with AD, IL-17RA mutation is associated with extrinsic type AD. So, early detection of IL-17RA mutation in patients with AD could help to predict the development of extrinsic type AD.