Enhancement of delayed hypersensitivity inflammatory reactions in guinea pig skin by 12(R)-hydroxy-5,8,14-eicosatrienoic acid.
Delayed-type hypersensitivity (DTH) reactions are initiated by sensitized T cells. Their progression is dependent upon the local release of various autacoids, including cytokines and eicosanoids, by T cells, infiltrating inflammatory cells, and resident tissue cells. 12(R)-hydroxy-5,8,14-eicosatrienoic acid [12(R)-HETrE], an eicosanoid produced by skin and cornea, possesses potent proinflammatory properties at picomolar concentrations including vasodilation, increase in membrane permeability, neutrophil chemotaxis, and angiogenesis. Because DTH reactions are associated with many of these same phenomena, we examined the effect of 12(R)-HETrE and related 12-hydroxyeicosanoids on the expression of DTH to purified protein derivative of tuberculin in sensitized guinea pigs. In the absence of purified protein derivative of tuberculin, none of the eicosanoids evoked erythema or edema after intradermal injection at doses up to 100 pmol. When injected together with purified protein derivative of tuberculin, 12(R)-hydroxy-5,8,10,14-eicosatetraenoic acid [12(R)-HETE], but not its enantiomer 12(S)-HETE, significantly inhibited macroscopic expression of delayed reactivity (erythema) only at the highest dose tested, 10 pmol. In contrast, 12(R)-HETrE significantly enhanced expression of DTH at doses between 1 fmol and 1 pmol (50% and 30% increases above control, respectively). Its stereoisomer, 12(S)-HETrE, did not enhance DTH at any tested dose, but was able to block the activity of 12(R)-HETrE when injected simultaneously. Enhancement or inhibition of visible skin responses was not associated with qualitative or quantitative changes in cellular infiltrates at the reaction site. 12(R)-HETrE had no effect on the nonimmunologic inflammatory skin reaction induced by phorbol myristate acetate, suggesting selectivity toward DTH. We conclude that 12(R)-HETrE enhances DTH via a yet to be determined mechanism and that its stereoisomer, 12(S)-HETrE, may be a useful antagonist for studying the inflammatory actions of this eicosanoid.
Conners
M S
MS
Department of Pharmacology, New York Medical College, Valhalla 10595.
Schwartzman
M L
ML
Quan
X
X
Heilman
E
E
Chauhan
K
K
Falck
J R
JR
Godfrey
H P
HP
D015126:8,11,14-Eicosatrienoic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D002199:Capillary Permeability / Q000187:drug effects; D003872:Dermatitis / Q000276:immunology; D004890:Erythema / Q000209:etiology / Q000276:immunology / Q000503:physiopathology; D006168:Guinea Pigs; D006968:Hypersensitivity, Delayed / Q000503:physiopathology*; D008297:Male; D012867:Skin / Q000187:drug effects* / Q000276:immunology*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014373:Tuberculin / Q000276:immunology
D014373:Tuberculin; C067514:12-hydroxy-5,8,14-eicosatrienoic acid; D015126:8,11,14-Eicosatrienoic Acid; D013755:Tetradecanoylphorbol Acetate