Suppressive effect of topically applied CX-659S, a novel diaminouracil derivative, on the contact hypersensitivity reaction in various animal models.

Abstract

BACKGROUND:

The T-cell-mediated contact hypersensitivity reaction (CHR) is thought to be involved in the pathogenesis of clinical cutaneous disorders including atopic dermatitis. A novel diaminouracil derivative, CX-659S, has been reported to have an inhibitory activity against picryl chloride (PC)-induced CHR when administered either orally or percutaneously. The inhibitory effect of topical CX-659S was assessed in three CHR models in the present study. In addition, to elucidate the mechanism of action of this compound, we examined the effect of CX-659S on the expression of messenger RNAs for proinflammatory cytokines after elicitation in PC models.

METHODS:

For the in vivo evaluation of the efficacy of CX-659S, we used PC- or oxazolone-induced CHR in mice and 2,4-dinitrochlorobenzene (DNCB)-induced CHR in guinea pigs. CX-659S was topically applied immediately after the hapten challenge in each model. To assess the effect on gene expression of cytokines, we used the reverse transcriptase-polymerase chain reaction (RT-PCR), a semiquantitative technique with specific primers.

RESULTS:

Topical CX-659S dose-dependently inhibited ear swelling at 24 h after the challenge in the two mouse models. This inhibitory effect was histologically confirmed in the PC model. Topically applied CX-659S also inhibited erythema and edema formation 24 h after challenge in the guinea pig model. CX-659S inhibited the expression of mRNA for proinflammatory cytokines IL-1 beta and TNF-alpha in vivo.

CONCLUSIONS:

Topically applied CX-659S showed significant inhibitory activities against CHR models both in mice and in guinea pigs. Inhibition profiles of CX-659S toward mRNA expression for proinflammatory cytokines corroborated these findings. CX-659S thus could be a useful therapeutic agent for allergic cutaneous disorders such as allergic contact dermatitis and atopic dermatitis.

• Authors: Y Goto, Y Inoue, M Tsuchiya, M Isobe, T Ueno, H Uchi, M Furue, H Hayashi
• Journal: International archives of allergy and immunology (Int Arch Allergy Immunol) Vol. 123 Issue 4 Pg. 341-8 (Dec 2000) ISSN: 1018-2438 [Print] Switzerland
• PMID: 11146392 (Publication Type: Journal Article)
• Copyright: Copyright 2000 S. Karger AG, Basel

Chemical References

• DNA Primers
• Dinitrochlorobenzene
• Immunosuppressive Agents
• Interleukin-1
• RNA, Messenger
• Tumor Necrosis Factor-alpha
• Oxazolone
• Uracil
• CX 659S

Topics

• Administration, Topical
• Animals
• Base Sequence
• DNA Primers (genetics)
• Dermatitis, Contact (drug therapy, etiology, pathology)
• Dinitrochlorobenzene (immunology, toxicity)
• Disease Models, Animal
• Guinea Pigs
• Humans
• Immunosuppressive Agents (administration & dosage)
• Interleukin-1 (genetics)
• Male
• Mice
• Mice, Inbred ICR
• Oxazolone (immunology, toxicity)
• RNA, Messenger (genetics, metabolism)
• Tumor Necrosis Factor-alpha (genetics)
• Uracil (administration & dosage, analogs & derivatives)