Abstract
T cells play a pivotal role in the initiation and progression of multiple sclerosis. We have found that 1,4-aryl-2-mercaptoimidazole (KRM-III) inhibited T-cell antigen receptor- and phorbol myristate acetate/ionomycin-induced activation of nuclear factor of activated T cells (NFAT) and T-cell proliferation with an IC50 of 5 μM. The KRM-III-mediated inhibitory effect was specific for NFAT activation but not for nuclear factor kB. Oral administration of 90 mg/kg KRM-III resulted in complete abrogation of anti-CD3 antibody-induced T-cell activation and a 45.8% reduction in footpad swelling in bovine serum albumin-induced delayed-type hypersensitivity. In the murine experimental autoimmune encephalomyelitis (EAE) model, oral administration of KRM-III significantly attenuated the severity of disease when given before or after disease onset. Draining lymph node cells from KRM-III-treated mice showed markedly reduced proliferation in response to myelin oligodendrocyte glycoprotein peptide. Histological analysis indicated that KRMIII reduced the infiltration of inflammatory cells to the white matter of spinal lumbar cords. These results demonstrate that KRM-III efficiently inhibits T-cell activation and inflammatory responses and lessens EAE clinical signs, which suggest KRMIII as a potential lead compound for the treatment of T-celldriven autoimmune diseases.
| Original language | English |
|---|---|
| Pages (from-to) | 1005-1013 |
| Number of pages | 9 |
| Journal | Journal of Pharmacology and Experimental Therapeutics |
| Volume | 331 |
| Issue number | 3 |
| DOIs | |
| Publication status | Published - 2009 Dec 1 |
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All Science Journal Classification (ASJC) codes
- Molecular Medicine
- Pharmacology
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Oral administration of 1,4-aryl-2-mercaptoimidazole inhibits T-cell proliferation and reduces clinical severity in the murine experimental autoimmune encephalomyelitis model. / Jung, Eun Joo; Hur, Minkyu; Kim, Young Lim; Lee, Ge Hyeong; Kim, Jeongmin; Kim, Ikyon; Lee, Min Woo; Han, Ho Kyun; Kim, Mi Soon; Hwang, Sejin; Kim, Sungjoo; Woo, A. Mi; Yoon, Yeup; Park, Heon Jin; Won, Jonghwa.
In: Journal of Pharmacology and Experimental Therapeutics, Vol. 331, No. 3, 01.12.2009, p. 1005-1013.Research output: Contribution to journal › Article
TY - JOUR
T1 - Oral administration of 1,4-aryl-2-mercaptoimidazole inhibits T-cell proliferation and reduces clinical severity in the murine experimental autoimmune encephalomyelitis model
AU - Jung, Eun Joo
AU - Hur, Minkyu
AU - Kim, Young Lim
AU - Lee, Ge Hyeong
AU - Kim, Jeongmin
AU - Kim, Ikyon
AU - Lee, Min Woo
AU - Han, Ho Kyun
AU - Kim, Mi Soon
AU - Hwang, Sejin
AU - Kim, Sungjoo
AU - Woo, A. Mi
AU - Yoon, Yeup
AU - Park, Heon Jin
AU - Won, Jonghwa
PY - 2009/12/1
Y1 - 2009/12/1
N2 - T cells play a pivotal role in the initiation and progression of multiple sclerosis. We have found that 1,4-aryl-2-mercaptoimidazole (KRM-III) inhibited T-cell antigen receptor- and phorbol myristate acetate/ionomycin-induced activation of nuclear factor of activated T cells (NFAT) and T-cell proliferation with an IC50 of 5 μM. The KRM-III-mediated inhibitory effect was specific for NFAT activation but not for nuclear factor kB. Oral administration of 90 mg/kg KRM-III resulted in complete abrogation of anti-CD3 antibody-induced T-cell activation and a 45.8% reduction in footpad swelling in bovine serum albumin-induced delayed-type hypersensitivity. In the murine experimental autoimmune encephalomyelitis (EAE) model, oral administration of KRM-III significantly attenuated the severity of disease when given before or after disease onset. Draining lymph node cells from KRM-III-treated mice showed markedly reduced proliferation in response to myelin oligodendrocyte glycoprotein peptide. Histological analysis indicated that KRMIII reduced the infiltration of inflammatory cells to the white matter of spinal lumbar cords. These results demonstrate that KRM-III efficiently inhibits T-cell activation and inflammatory responses and lessens EAE clinical signs, which suggest KRMIII as a potential lead compound for the treatment of T-celldriven autoimmune diseases.
AB - T cells play a pivotal role in the initiation and progression of multiple sclerosis. We have found that 1,4-aryl-2-mercaptoimidazole (KRM-III) inhibited T-cell antigen receptor- and phorbol myristate acetate/ionomycin-induced activation of nuclear factor of activated T cells (NFAT) and T-cell proliferation with an IC50 of 5 μM. The KRM-III-mediated inhibitory effect was specific for NFAT activation but not for nuclear factor kB. Oral administration of 90 mg/kg KRM-III resulted in complete abrogation of anti-CD3 antibody-induced T-cell activation and a 45.8% reduction in footpad swelling in bovine serum albumin-induced delayed-type hypersensitivity. In the murine experimental autoimmune encephalomyelitis (EAE) model, oral administration of KRM-III significantly attenuated the severity of disease when given before or after disease onset. Draining lymph node cells from KRM-III-treated mice showed markedly reduced proliferation in response to myelin oligodendrocyte glycoprotein peptide. Histological analysis indicated that KRMIII reduced the infiltration of inflammatory cells to the white matter of spinal lumbar cords. These results demonstrate that KRM-III efficiently inhibits T-cell activation and inflammatory responses and lessens EAE clinical signs, which suggest KRMIII as a potential lead compound for the treatment of T-celldriven autoimmune diseases.
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U2 - 10.1124/jpet.109.154948
DO - 10.1124/jpet.109.154948
M3 - Article
C2 - 19741152
AN - SCOPUS:73349127476
VL - 331
SP - 1005
EP - 1013
JO - Journal of Pharmacology and Experimental Therapeutics
JF - Journal of Pharmacology and Experimental Therapeutics
SN - 0022-3565
IS - 3
ER -