담배 니코틴에 의한 사람 태아 성상세포에서 종양괴사인자(TNF-α)의 발현 억제작용

손일홍,이성익,양현덕,한선정,석승한,이재규,김재현,박주영,문형인,이성수,Son, Il-Hong,Lee, Sung-Ik,Yang, Hyun-Duk,Han, Sun-Jung,Suk, Seung-Han,Lee, Jai-Kyoo,Kim, Jae-Hyun,Park, Joo-Young,Moon, Hyung-In,Lee, Sung-Soo 대한화학회 2007 대한화학회지 Vol.51 No.3

니코틴은 사람 대식세포에서 interleukin 2 (IL-2)와 종양괴사인자 (tumor necrosis factor-alpha; TNF-α) 가 생성되는 것을 억제하는데, 이러한 억제작용은 cytokine 유전자 발현 중 전사단계에서 전사인자의 활성을 억제함으로써 일어난다. 이러한 니코틴의 면역반응 억제작용은 아프타성궤양 및 궤양성대장염, 알레르기성폐 포염, 건초열 등에서도 보고되고 있다. 만일 중추신경계에서도 위와 같은 니코틴의 면역억제 작용이 일어난 다면 다발성경화증과 같은 면역반응 매개질환의 치료에 새로운 전기가 마련될 수 있을 것이다. 본 연구에서 는 중추신경계의 여러 면역반응 매개질환의 병태생리에 대한 이해를 넓히고자, 이미 알려진 니코틴의 cytokine 생성억제가 사람 중추신경계의 성상세포에서도 일어남을 확인하고 그 억제기전을 밝히고자 하였다. 이를 위 하여 사람 태아 성상세포에 다양한 농도의 니코틴과 IL-1β를 처리한 다음 TNF-α mRNA의 발현 정도와 NF- κB의 활성을 비교, 분석하여 다음과 같은 결과를 얻었다. 1. 사람 태아 성상세포를 0.1-20 μg/ml의 니코틴으로 처리해 본 결과 10 μg/ml 이상의 농도에서 세포독성능이 나타나기 시작하였다. 2. 사람 태아 성상세포에 IL- 1β를 처리하면 2시간만에 TNF-α mRNA가 최대로 발현되었으며 그 이후로는 점진적으로 감소하였다. 3. 사 람 태아 성상세포를 1 및 0.1 μg/ml의 니코틴으로 전처리한 후 IL-1β로 자극한 군에서는 IL-1β 단독 처리군에 비해 TNF-α mRNA의 발현이 감소하는 양상을 보였다. 1 μg/ml의 니코틴을 처리한 경우에는 8시간 이후부터 TNF-α mRNA의 발현이 현저하게 감소하여 12시간에 최대로 감소하였다. 또한 0.1 μg/ml의 니코틴을 처리한 군에서는 24시간에 가장 현저하게 감소하였다. 4. 성상세포에 IL-1β로 처리한 군에서는 강력한 NF-κB의 활성 을 확인할 수 있었으며, 니코틴을 전처리하고 IL-1β 자극한 군에서는 NF-B의 활성이 감소하였다. 결론적으로 일정농도 이상의 니코틴은 세포독성효과를 나타내나 적정한 농도와 시간 경과후 니코틴은 사람 태아 성상세포에서 IL-1β에 의해 유도되는 TNF-α의 발현 감소를 유도하며, 이는 NF-κB의 활성을 감소시킴으로써 나타난다고 생각된다. The Tumor necrosis factor-α, (TNF-α), is involved in the pathogenesis of multiple sclerosis and contributes to the degeneration of oligodendrocytes as well as neurons. Nicotine has been found to have immunosuppressive and inflammation-suppressing effects. Astrocytes, the major glial cells in the CNS, are capable of producing TNF-α at both the mRNA and protein levels in response to interleukin-1 (IL-1) or TNF-α. Nicotine has been shown to influence glial cell functions. To order to explore the role of astrocytes in the production of TNF-α, astrocytes were pretreated with nicotine and are stimulated with IL-1β to determine their effects on TNF-α production. The results are as follows. Cytotoxic effects of nicotine on human fetal astrocytes were noted above 10 μg/ml of nicotine. The effect of IL-1β on TNF-α mRNA expression in primary cultured human fetal astrocytes was maximal at 2 h after IL- 1β(100 pg/ml) treatment. Human fetal astrocytes were pretreated with 0.1, 1, and 10 μg/ml of nicotine and then stimulated with IL-1β (100 pg/ml) for 2 h. The inhibitory effect of nicotine on expressions of TNF-α mRNA in human fetal astrocytes with pretreated 0.1 μg/ml of nicotine is first noted at 8 hr, and the inhibitory effect is maximal at 12 h. The inhibitory effect at 1 μg/ml of nicotine is inhibited maximal at 24 h. Nicotine at 0.1, 1 and 10 μg/ml concentrations significantly inhibits IL-1β-induced NF-κB activation. Collectively, this study indicates that nicotine might inhibit the expression of TNF-α in activated human fetal astrocytes.

Early Phase of UVB - induced GM - CSF Upregulation in Epithelial Cell Line is not Totally Dependent on IL - 1α

Park, Kyoung Chan,Kim, Kyu Han,Ahn, Jong Seong,Chung, Jin Ho,Youn, Jai Il,Whang, Ji Hwan,Youn, Sang Woong,Kim, Young Gull,Koh, Woo Seok,Jung, Hyun Chae 대한피부과학회 1997 Annals of Dermatology Vol.9 No.4

Backgrounds : It was demonstrated that ultraviolet(UV) B light induces the release of IL-la in cultured human epithelial cell line and augmentation of GM-CSF production by UVB is reported to be mediated by IL-1α in the murine keratinocyte cell line Pam 212. Objective : The purpose of this study was to evaluate the effects of UVB on kinetic profile of IL-1 and GM-CSF mRNA expression and to see whether synthesis of GM-CSF by UVB can be completely inhibited by blocking IL-1α mediated pathway. Method : We used a competitive RT-PCR for measuring cytokine gene expression in epithelial cell line after UV radiation. Results : The IL-1α mRNA increased as early as 1h after UV irradiation, and then decreased at 3h after the irradiation. Thereafter, the response of IL-1α mRNA was upregulated with a second peak at 6h after the UV irradiation. However, mRNA for GM-CSF increased at 1h after UV light exposure and anti-IL-1α antibodies could only partially inhibit UV-augmented GMCSF production. Conclusion : UVB induced GM-CSF production seemed to be mainly mediated by UVB induced IL-1α but these results suggest that UVB may also induce GM-CSF production through an IL-1α independent pathway.

인체 각질형성세포의 Interleukin-6 생산에 미치는 UVB, UVA 및 PUVA의 영향

고우석,김규한,정진호,윤상호,윤재일,은희철 大韓免疫學會 1996 大韓免疫學會誌 Vol.18 No.3

Huma Keratinocytes are capable of producing a wide variety of cytokines and growth factors that may act as mediator in an immune response and play an important role in proliferation and repair. Production of epidermal cytokines may be induced by bacterial products, by other proinflammatory cytokines, or by physical alteration including ultraviolet radiation. In the present study, we investigated the effect of UVA and PUVA on the production of IL-6 by cultured human keratinocyte. Human keratinocytes derived from normal foreskin were treated with various dose of UVB, UVA and PUVA. With the irradiated keratinocytes or culture supernatant we measured the expression of IL-6 mRNA and the production of IL-6. The result of - the present study was that the UVB increased the production of IL-6 but UVA and PUVA didn't increase the production of IL-6 by human keratinocyte.

자외선 조사 후의 인체 각질형성세포에서의 IL-1 생산 및 Retinoid가 이에 미치는 영향

정진호,은희철,윤재일 大韓免疫學會 1993 大韓免疫學會誌 Vol.15 No.-

The purpose of this study is to observe the effect of UVB and retinoid on the production of IL-1 in cultured human keratinocytes and to determine whether retinoid can influence the effect of UVB on the IL-1 production. Human keratinocytes derived from normal foreskin were treated with various dose of UVB(0-100mJ/cm2) or retinol acetate(0-5 x 10-6M) and cultured for 1-3 days. IL-i levels in the culture supernatants and cell extracts of the cultured keratinocytes were measured by thymocyte costimulation assay. We demonstrated that UVB and retinol acetate increased the production of IL-1 by human keratinocytes, and the stimulatory effect of UVB on the production of IL -1 in keratinncvt.es was also increased by retinnl acetate.

Interleukin-4와 히스타민이 알레르기성 비염과 비 알레르기성 비염에서 비점막 섬유아세포에 미치는 영향

김성완,조중생,박재경,차창일,김광일 대한이비인후과학회 1999 대한이비인후과학회지 두경부외과학 Vol.42 No.3

Nicotine Suppresses TNF-${\alpha}$ Expression in Human Fetal Astrocyte through the Modulation of Nuclear Factor-${\kappa}B$ Activation

Son, Il-Hong,Park, Yong-Hoon,Yang, Hyun-Duk,Lee, Sung-Ik,Han, Sun-Jung,Lee, Jai-Kyoo,Ha, Dae-Ho,Kang, Hyung-Won,Park, Joo-Young,Lee, Sung-Soo The Korean Society of Toxicogenomics and Toxicopro 2008 Molecular & cellular toxicology Vol.4 No.2

Parkinson's disease (PD) progresses severely by a gradual loss of dopaminergic neurons in the substantia nigra (SN). Epidemiological studies showed that the incidences of PD were reduced by smoking of which the major component, nicotine might be neuroprotective. But the function of nicotine, which might suppress the incidences of PD, is still unknown. Fortunately, recently it was reported that a glial reaction and inflammatory processes might participate in a selective loss of dopaminergic neurons in the SN. The levels of tumour necrosis factor (TNF)-${\alpha}$ synthesised by astrocytes and microglia are elevated in striatum and cerebrospinal fluid (CSF) in PD. TNF-${\alpha}$ kills the cultured dopaminergic neurons through the apoptosis mechanism. TNF-${\alpha}$ release from glial cells may mediate progression of nigral degeneration in PD. Nicotine pretreatment considerably decreases microglial activation with significant reduction of TNF-${\alpha}$ mRNA expression and TNF-${\alpha}$ release induced by lipopholysaccharide (LPS) stimulation. Thus, this study was intended to explore the role of nicotine pretreatment to inhibit the expressions of TNF-${\alpha}$ mRNA in human fetal astrocytes (HFA) stimulated with IL-$1{\beta}$. The results are as follows: HFA were pretreated with 0.1, 1, and $10{\mu}g/mL$ of nicotine and then stimulated with IL-$1{\beta}$ (100 pg/mL) for 2h. The inhibitory effect of nicotine on expressions of TNF-${\alpha}$ mRNA in HFA with pretreated $0.1{\mu}g/mL$ of nicotine was first noted at 8hr, and the inhibitory effect was maximal at 12 h. The inhibitory effect at $1{\mu}g/mL$ of nicotine was inhibited maximal at 24 h. Cytotoxic effects of nicotine were noted above $10{\mu}g/mL$ of nicotine. Moreover, Nicotine at 0.1, 1 and $10{\mu}g/mL$concentrations significantly inhibited IL-$1{\beta}$-induced TF-${\kappa}B$ activation. Collectively, these results indicate that in activated HFA, nicotine may inhibit the expression of TNF-${\alpha}$ mRNA through the pathway which suppresses the NF-${\kappa}B$ activation. This study suggests that nicotine might be neuroprotective to dopaminergic neurons in the SN and reduce the incidences of PD.

Poster Session : PS 0694 ; Rheumatology ; Appearance of Psoriasis after TNF-a Blocker and Use of Ustekinumab or Tocilizumab for Refractory Monoarthritis

( Jin Young Moon ),( Dong Jin Go ),( Jae Hyun Lee ),( Jin Kyun Park ),( Eun Bong Lee ),( Yeong Wook Song ),( Jai Il Youn ),( Eun Young Lee ) 대한내과학회 2014 대한내과학회 추계학술대회 Vol.2014 No.1

Nowadays, tumor necrosis factor-a (TNF-a) blockers are used for the treatment of RA, infi ammatory bowel diseases (IBD), ankylosing spondylitis (AS), psoriatic arthritis (PsA), and psoriasis. Paradoxically, there are some reports of appearance of psoriasis after TNF-a blockers. We report a patient who have seronegative mono-rheumatoid arthritis (mono-RA) on knee joint that experienced psoriasis after TNF-a blocker therapy (adalimumab and etanercept). For the patient, oral medication is not available due to intolerance; thus, we tried ustekinumab which is an anti-IL-12/23 monoclonal antibody that has been used to treat psoriasis. After ustekinumab injection, psoriatic skin lesions and joint symptoms were much improved in the patient. But in the following period, joint pain and swelling aggravated and synovial fi uid cytokine levels such as IL-6 and IL-17 were elevated. Treatment was changed to tocilizumab, humanized monoclonal antibody against IL-6 receptor. After injection, knee joint swelling rapidly subsided without worsening of psoriatic skin lesion.

Paradoxical psoriasis induced by biologic therapies

( Hyun Yi Suh ),( Hong Lim Kim ),( Kyung Ho Kim ),( Jae Wook Jeon ),( Ji Young Ahn ),( Mi Youn Park ),( Jai Il Youn ) 대한피부과학회 2015 대한피부과학회 학술발표대회집 Vol.67 No.1

Biologic therapies currently approved for the treatment of moderate-to-severe plaque psoriasis work well. Administrations of those are beneficial in a variety of chronic inflammatory conditions. Recent reports have illustrated the paradoxical development of psoriasis after biologic therapies. A 30-year-old man presented widespread scaly erythematous patches on the whole body involvement after treatment with the third dose of infliximab. He was diagnosed with palmoplantar psoriasis 6 years ago. The patients had been treated either neotigason or cyclosporine with eximer phototherapy for 2 years 6 months before visiting our psoriasis clinic. He was started on the injections of infliximab, but there was no improvement after the first dose. After receiving third dose of infliximab, the patient had experienced worsening of his plaque psoriasis on the whole. We changed other biologics, ustekinumab, anti-IL-12/23 p40 monoclonal antibody. He was treated with ustekinumab. Although receiving the second dose of ustekinumab, the skin lesions were not improved and worsening of appearing pustules on the palm and sole. We treated with cyclosporin and with calcipotriol agent (Daivonex® cream) for his skin lesion. Herein, we report this impressive case of induced paradoxical psoriasis after treating on TNF-a inhibitor and IL-12/23 inhibitor.

Case Reports : Appearance of Psoriasis after Tumor Necrosis Factor-α Blocker and Use of Ustekinumab or Tocilizumab for Refractory Monoarthritis

( Jinyoung Moon ),( Nakwon Kwak ),( Jin Lim ),( Dong Jin Go ),( Jae Hyun Lee ),( Jin Kyun Park ),( Eun Bong Lee ),( Yeong Wook Song ),( Jai Il Youn ),( Eun Young Lee ) 대한류마티스학회 2015 대한류마티스학회지 Vol.22 No.4

Nowadays, tumor necrosis factor-α (TNF-α) blockers are used for treatment of rheumatoid arthritis, inflammatory bowel diseases, ankylosing spondylitis, psoriatic arthritis, and psoriasis. Paradoxically, there are some reports on the appearance of psoriasis after administration of TNF-α blockers. Here, we report on a patient with monoarthritis in a knee joint who experienced psoriasis after TNF-α blocker therapy (adalimumab and etanercept). Oral medication was not a treatment option due to patient intolerance; thus, we tried ustekinumab, an anti-interleukin (IL)-12/23 monoclonal antibody used for treatment of psoriasis. Following ustekinumab injection, psoriatic skin lesions and joint symptoms were much improved. However, in the following period, joint pain and swelling became aggravated and synovial fluid cytokine levels including IL-6 and IL-17 were elevated. The treatment was changed to tocilizumab, a humanized monoclonal antibody against IL-6 receptor. After injection, knee joint swelling rapidly subsided without worsening of psoriatic skin lesions. (J Rheum Dis 2015;22:263-268)

Histoid Leprosy의 1例

尹在一,金鍾敏,金洪植,金道一 大韓癩學會 1976 癩學 會誌 Vol.10 No.1