Premium
Vascular endothelial growth factor receptor tyrosine kinase inhibitor PTK787/ZK 222584 inhibits both the induction and elicitation phases of contact hypersensitivity
Author(s) -
YAMAMOTO Aisaku,
WATANABE Hideaki,
SUEKI Hirohiko,
NAKANISHI Takako,
YASUHARA Hajime,
IIJIMA Masafumi
Publication year - 2007
Publication title -
the journal of dermatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.9
H-Index - 65
eISSN - 1346-8138
pISSN - 0385-2407
DOI - 10.1111/j.1346-8138.2007.00304.x
Subject(s) - sensitization , vascular endothelial growth factor , tyrosine kinase , medicine , flow cytometry , tyrosine kinase inhibitor , chemistry , receptor , pharmacology , endocrinology , immunology , vegf receptors , cancer
Vascular endothelial growth factor (VEGF) and its endothelial cell receptors (VEGFR) have been shown to be involved in the pathogenesis of the contact hypersensitivity (CHS) reaction. Previous studies have demonstrated that anti‐VEGFR‐2 antibody significantly suppresses the elicitation phase of CHS but does not affect the induction phase. PTK787/ZK 222584 (1‐[4‐chloroanilino]‐4‐[4‐pyridylmethyl] phthalazine succinate; PTK/ZK ) is a potent inhibitor of VEGFR tyrosine kinases. To test the effect of PTK/ZK on the induction and elicitation phases of CHS separately, we used an established method of CHS assay‐sensitization and challenge in BALB/c mice. Either 50 mg/kg/day PTK/ZK or vehicle serving as a control was administered orally in the induction or elicitation phases separately. In the afferent phase, flow cytometry of skin‐draining lymph node cells revealed that the migration of Langerhans cells was suppressed in the mice treated with PTK/ZK at sensitization. The degrees of ear swelling at 24 and 48 h were significantly diminished in mice treated with PTK/ZK at sensitization ( P < 0.05). In the efferent phase, the degrees of ear swelling at 24 h ( P < 0.01) and 48 h ( P < 0.05), ear blood flow at 24 and 48 h ( P < 0.01), and production of VEGF in the epidermis at 24 h ( P < 0.05) were significantly suppressed in mice treated with PTK/ZK at elicitation. These findings and previous demonstrations suggest that both VEGF R‐1 and VEGF R‐2 are needed during the induction phase, and that VEGFR‐2 has a pivotal role in the elicitation phase of the CHS reaction.