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.

IL-33-matured dendritic cells promote Th17 cell responses via IL-1β and IL-6

Park, Su-Ho,Kim, Myun Soo,Lim, Hui Xuan,Cho, Daeho,Kim, Tae Sung Elsevier 2017 Cytokine Vol.99 No.-

<P><B>Abstract</B></P> <P>IL-33 is associated with a variety of autoimmune diseases, such as sclerosis, inflammatory bowel disease, and rheumatoid arthritis. Although IL-33 is mainly involved in the induction of Th2 cells, however, the relationship between IL-33 and Th17 cells is still largely unknown. In this study, we investigated the effects of IL-33 on DC-mediated CD4<SUP>+</SUP> T cell activation and Th17 cell differentiation because DCs are essential cells for presenting self-antigens to CD4<SUP>+</SUP> T cells in autoimmune disease conditions. OT-II mice were injected with IL-33-treated DCs or untreated DCs that were primed by OVA<SUB>323-339</SUB> peptide, and their Th17 cell responses were compared. Th17 cell population and IL-17 expression levels were significantly increased in draining lymph nodes of mice injected with IL-33-treated DCs, compared with those in mice injected with untreated DCs. IL-33 treatment maturated DCs to present self-antigens and to increase production of proinflammatory cytokines such as IL-1β and IL-6, which have a crucial role in Th17 cell differentiation. We found that the IL-33-matured DCs enhanced the expression of an early T cell activation marker (CD69) and the Th17 master transcription factor (RORγt), but IL-33 did not directly affect CD4<SUP>+</SUP> T cell differentiation or increase Th17 polarization. Notably, neutralizing IL-1β and/or IL-6 significantly decreased IL-17 expression levels and Th17 cell population which were increased by the coculture of CD4<SUP>+</SUP> T cells with IL-33-matured DCs, indicating that IL-33 may induce Th17 cell responses via IL-1β and IL-6 derived from IL-33-matured DCs.</P> <P><B>Highlights</B></P> <P> <UL> <LI> IL33 enhances Th17 cell differentiation through DC maturation. </LI> <LI> IL33 does not directly induce differentiation of naïve CD4<SUP>+</SUP> T cells to Th17 cells. </LI> <LI> IL33-matDCs increase surface molecule-expressions driving T cell activation. </LI> <LI> IL33-matDCs promote Th17 cell responses via DC-derived IL-1β and IL-6. </LI> </UL> </P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>

IL-17 axis accelerates the inflammatory progression of obese in mice via TBK1 and IKBKE pathway

Lee, Seung Hoon,Jhun, JooYeon,Byun, Jae-Kyung,Kim, Eun-Kyung,Jung, KyoungAh,Lee, Ji Eun,Choi, Jong Young,Park, Sung-Hwan,Cho, Mi-La Elsevier 2017 Immunology letters Vol.184 No.-

<P><B>Abstract</B></P> <P>Obesity mediates immune inflammatory response and induces IL-17 expression. Adipgenesis can be regulated by IL-17 and it causes TBK1 activation. The inhibition of TBK1 and the inhibition of I IKBKE reduces inflammatory response and improves obesity. It is hypothesized that IL-17 deficiency inhibits obesity progression and inflammation. 3T3-L1 preadipocytes were differentiated in vitro and treated with IL-17. RAW264.7 cells and differentiated 3T3-L1 were pretreated with TBK1 inhibitor and then stimulated with IL-17. Wild-type and IL-17 knock out mice were fed with high-fat diet. IL-17 inhibits adipocyte differentiation from mouse-derived 3T3-L1 preadipocytes and reduces mRNA expression of proadipogenic transcription factors and adipokines in adipocyte cells. IL-17 also showed up-regulation of mRNA levels of inflammatory cytokines in RAW cells. The inhibitor of TBK1 and IKBKE attenuates the effect of IL-17. Loss of IL-17 deficiency improves diet-induced obesity, fatty liver, glucose and lipid metabolism in mice. The expression of TBK1 and IKBKE decreased in the spleen and liver of IL-17 deficiency mice. Moreover, the inflammatory response within the visceral adipose tissue and Th1 cells were inhibited, however, M2 macrophage and Th2 cells increased in IL-17 deficiency mice. IL-17 inhibits adipogenesis where a lack of IL-17 ameliorates glucose metabolism. As well, the inhibition of TBK1 reduces inflammation induced by IL-17. Therefore, IL-17 may be involved in the development of obesity and metabolic dysfunction in a TBK1-dependent manner.</P> <P><B>Highlights</B></P> <P> <UL> <LI> IL-17 induced TBK1-mediates immune inflammatory response in adipocytes and downregulated adipocyte differentiation. </LI> <LI> Loss of IL-17 reduced inflammation and improved fatty liver in obesity animal model. </LI> <LI> The inhibition of TBK1 could decrease inflammatory response in RAW 264.7 cells. </LI> </UL> </P>

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.

Signaling Through the Murine T Cell Receptor Induces IL-17 Production in the Absence of Costimulation, IL-23 or Dendritic Cells

Sarah L. Gaffen,Xikui K. Liu,James L. Clements 한국분자세포생물학회 2005 Molecules and cells Vol.20 No.3

IL-17 (IL-17A or CTLA-8) is the founding member of a novel family of inflammatory cytokines, and emerging evidence indicates that it plays a central role in inflammation and autoimmunity. IL-17 is made primarily, if not exclusively by T cells, but relatively little is known about how its expression is regulated. in the present study, we examined the requirements and mechanisms for IL-17 expression in primary mouse lymphocytes. Like many cytokines, IL-17 is induced rapidly in primary T cells after stimulation of the T cell receptor (TCR) through CD3 crossinking. Surprisingly, however, the pattern of regulation of IL-17 is different in mice than in humans, because “costimulation”of T cells through CD28 only mildly enhancedIL-17 expression, whereas levels of IL-2 were dramatically enhanced. Similarly, several other costimulatory molecules such as ICOS, 4-1BB and CD40L exerted only very weak enhancing effects on IL-17 production. In agreement with other reports, IL-23 enhanced CD3-induced IL-17 expression. However, IL-17 production can occur autonomously in T cells, as neither dendritic cells nor IL-23 were necessary for promoting shortterm production of IL-17. Finally, to begin to characterize the TCR-mediated signaling pathway(s) required for IL-17 production, we showed that IL-17 expression is sensitive to cyclosporin-A and MAPK inhibitors, suggesting the involvement of the calcineurin/

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.

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.

창이자 추출물이 아토피 피부염 유발 생쥐의 비장 세포 Th17의 세포분화 억제에 따른 아토피 피부 상태에 미치는 영향

김금란(Kim, Kum-Lan),최태부(Choe, Tae-Boo) 한국생물공학회 2009 KSBB Journal Vol.24 No.4

아토피피부염 (AD)은 천식, 음식 알레르기, 비염 같은 전신아토피질환을 동반하는 만성재발성 피부염증질환이다. 아토피피부염과 관련된 IL-17의 임상적 역할은 다양한 조건에서 보고되고 있으며, 또한 건선 피부 상태에 깊숙이 관여하고 있다. IL-17은 각질세포 (keratinocytes)에서 과잉으로 생산되며, 아토피피부염의 말초임파구에서도 다량 생성 됨을 세포내염색을 통하여 확인된 바 있다. 본 연구에서는 창이자 추출물 (XS-E와 XS-FL)이 NC/Nga 생쥐의 CD4<SUP>+</SUP> T 세포에서 유도된 Th17 세포의 분화억제 및 IL-17의 생산량 감소 효과에 대한 실험을 하였다. 그 결과 XS-E와 XS-FL을 처리한 섬유아세포에서 세포독성은 나타나지 않았고, 4일간 XS-E와 XS-FL에 동시배양 한 CD4<SUP>+</SUP> T 세포 의 IL-17 생산량을 FACS로 분석한 결과 100 μg/mL XS-E 처리군의 IL-17 생산량은 32.3%로 대조군에 비하여 2배 이상의 감소를 나타내었으며, 20 μg/mL XS-30% AFL (acetone XS-FL) 처리군의 Th17 세포는 19.6%으로 대조군에 비하여 3.5배 억제되었다. 또한 real-time PCR을 이용하여 IL-17A와 IL-22 mRNA의 유전자 발현량을 비교 분석한 결과, IL-17A와 IL-22 mRNA의 유전자발현의 RQ값은 XS-E와 XS-30% AFL를 처리한 실험군이 대조군에 비하여 유의성 있는 감소를 나타내었다(p < 0.01, p < 0.001). ELISA로 측정한 IL-17A 생산량은 XS-E와 XS-30% AFL를 처리한 실험군이 대조군에 비하여 현저히 감소 (p < 0.05, p < 0.001)하였다. Th17 세포의 증식을 알아보기 위하여, rIL-6와 TGF-β로 분화시킨 Th17 세포를 CFSE로 표지한 후 rIL-23 처리를 하여 4일간 배양하여 증식을 유도시켰다. 대조군의 Th17 세포 분열은 4일 동안 4번에 걸쳐 비슷한 세포수의 증식이 일어나는 것을 CFSE를 통하여 확인하였고, XS-30% AFL 처리군은 CFSE의 형광 분포가 점점 감소하여 Th17 세포의 증식이 억제됨을 알 수 있었다. Xanthii fructus which is well known as “Chang-ihjah” in Korea is the dried fruit of Xanthium strumarium L. (or Xanthium sibiricum PATR. Ex WIDD., Asteraceae. XS). Water extract of this fruit has been used for treatment of various inflammatory diseases such as tympanitis, allergic rhinitis, or ozena as alternative therapy material usually by oral administration in far Eastern countries including Korea. In this study, the effect of XS extract (XS-E) or XS-30% acetone fraction layer (XS-30% AFL) on the differentiation of CD4<SUP>+</SUP> T cells isolated from NC/Nga mouse and the production of IL-17 was investigated. The experimental results showed that 100 μg/mL of XS-E could decrease the production of IL-17 by CD4<SUP>+</SUP> Th17 cells by 2 fold and only 20 μg/mL of XS-30% AFL could inhibit 3.5 fold. The amount of IL-17A and IL-22 mRNA determined by real-time PCR was decreased remarkably when XS-E or XS-30% AFL was treated on CD4<SUP>+</SUP> Th17 cells(p<0.01, p<0.001). The amount of IL-17A protein determined by ELISA was also decreased remarkably(p<0.05, p<0.001). To study the effect of XS-E or XS-30% AFL on the proliferation of Th17 cells, CD4+ T cells of a NC/Nga mouse was firstly differentiated by rIL-6/TGF-β and then stimulated by rIL-23. The control group of Th17 cells were doubled every each day, while those of XS-E or XS-30% AFL treated group were shown to be delayed remarkably by these extracts. In conclusion, XS can inhibit the differentiation of Th17 cells of NC/Nga mouse and the production of IL-17 successfully, which may be a beneficial result for the treatment of atopic skin dermatitis.

류마티스 관절염 동물 모델에서 활막의 RANKL/OPG mRNA 발현 비율 및 IL-17의 효과

이준희 ( Jun Hee Lee ),김근태 ( Geun Tae Kim ),류선 ( Sun Ryu ),김주인 ( Ju In Kim ),백승훈 ( Seung Hoon Baek ),김성일 ( Sung Il Kim ) 대한류마티스학회 2006 대한류마티스학회지 Vol.13 No.2

Objective: To investigate the synovial mRNA expression of receptor activator of NFκB (RANK), RANK ligand (RANKL), osteoprotegerin (OPG) and RANKL/OPG mRNA expression ratio, and to evaluate the effects of IL-17 in experimental rheumatoid arthritis (RA) model. Methods: After induction of collagen-induced arthritis (CIA) by type II collagen in DBA1 mice, mice were anesthetized at day 28 and a small aperture in the skin of the knee was performed. Mice, in which arthritis of knee was present, were selected and divided into 3 groups, and phosphate-buffered saline (PBS group), IL-17 (IL-17 group) or anti-IL-17 monoclonal antibody (anti-IL-17 group) was injected to both knee joint at day 28 and 32. At day 35, mice were sacrificed and synovium of knee joints were isolated. Synovial mRNA expression of RANKL, RANK and OPG was assessed by real-time RT-PCR and immunohistochemical stain. Results: Synovial RANKL and RANK mRNA expressions were significantly different among IL-17, PBS, anti-IL-17 and normal group (IL-17>PBS>anti-IL-17>normal group), and synovial OPG mRNA expressions in PBS, IL-17 and anti-IL-17 group were significantly high than those in normal group, however, there was no significant difference among IL-17, PBS and anti-IL-17 group. RANKL/OPG mRNA ratio was significantly different among these groups (IL-17>PBS>anti-IL-17>normal group). In immunohistochemical stain, RANKL, RANK and OPG-positive cells were expressed at synovium. Conclusion: Synovial RANKL/OPG mRNA ratio was enhanced in CIA, and IL-17 induced higher RANKL/OPG ratio in the synovium of CIA, which was blocked by anti-IL-17 antibody. These results suggest that RANKL/OPG mRNA ratio play an important roles on bone destruction, and IL-17 may be actively involved in bone destruction by enhancing RANKL/OPG ratio in CIA model.