Molecular mechanisms of cis-urocanic acid and permethrin-induced alterations in cutaneous immunity.
OBJECTIVE
Cutaneous cis-urocanic acid (cUCA) or ultraviolet B exposure has been shown to cause diminished cutaneous contact hypersensitivity (CH) and to induce systemic tolerance (increased regulatory T lymphocytes) in mice. Permethrin is also a known CH inhibitor, but the molecular mechanisms are currently poorly understood. In this study, CH was evaluated in four strains of mice: an immunosensitive strain (C57BL/6N), an immunoresistant strain (SvImJ), a strain developed from C57BL/6N mice but genetically altered at both the tumor necrosis factor-alpha receptors (TNFalphap55R and p75R), and a strain developed from C57BL/6N but genetically deleted at the interferon-gamma (IFNgamma) locus.


METHODS
CH was evaluated in each group via oxazolone challenge following a 5-day exposure to intradermal (ID) cUCA or a single exposure to topical permethrin, or co-exposure to both chemicals in 5-week-old female C57BL/6N, SvImJ, and C57BL/6N mice genetically altered at the TNFalpha or IFNgamma locus.


RESULTS
A 5-day exposure to ID cUCA or a single exposure to topical permethrin resulted in diminished CH response in C57BL/6N mice, and this effect was exacerbated with concurrent exposure to both chemicals. CH in SvImJ was both cUCA- and permethrin-resistant relative to C57BL/6N mice, as 5-day cUCA or a single exposure to permethrin did not diminish CH, nor did concurrent exposure to cUCA and permethrin. Mice deleted at both TNFalphaR loci displayed similar but somewhat blunted diminished CH responses to cUCA or permethrin. This trend became significant with combined chemical exposure. IFNgamma knockout mice displayed similar diminished CH responses to cUCA or permethrin alone. Unlike C57BL/6N mice, the IFNgamma knockout mice did not show a further reduction in CH with combined chemical exposure.


CONCLUSIONS
These results suggest the following: (1)Mouse strains show variable susceptibility to permethrin- and cUCA-induced immunomodulation. (2)TNFalpha may be involved in the immunomodulatory effects of cUCA and permethrin. (3)IFNgamma may be required for the more than additive depression of CH caused by cUCA+permethrin.
Prater
M R
MR
Edward Via Virginia College of Osteopathic Medicine, 2265 Kraft Drive, Blacksburg, VA 24060, USA. rprater@evvcom.org
Blaylock
B L
BL
Holladay
S D
SD
D000276:Adjuvants, Immunologic / Q000008:administration & dosage / Q000494:pharmacology*; D000279:Administration, Cutaneous; D000818:Animals; D003877:Dermatitis, Contact / Q000276:immunology* / Q000473:pathology; D005260:Female; D007271:Injections, Intradermal; D016898:Interferon-alpha / Q000187:drug effects / Q000528:radiation effects; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D026023:Permethrin / Q000008:administration & dosage / Q000494:pharmacology; D012867:Skin / Q000187:drug effects / Q000276:immunology* / Q000528:radiation effects; D014409:Tumor Necrosis Factor-alpha / Q000187:drug effects / Q000528:radiation effects; D014466:Ultraviolet Rays; D014560:Urocanic Acid / Q000008:administration & dosage / Q000494:pharmacology*
D000276:Adjuvants, Immunologic; D016898:Interferon-alpha; D014409:Tumor Necrosis Factor-alpha; D026023:Permethrin; D014560:Urocanic Acid