On the other hand, the immortalized human skin cell line HaCaT expresses BLT2 receptors and responds to ultraviolet B (UVB) radiation by generating toxic reactive oxygen species which in turn cause the HaCaT cells to die by activating apoptotic pathways in a BLT2 receptor-dependent reaction. Topical treatment of mouse skin with a BLT2 receptor antagonist, LY255283, protects against UVB radiation-induced apoptosis and BLT2-overexpressing transgenic mice exhibited significantly more extensive skin apoptosis in response to UVB irradiation. Furthermore, 12-HHT inhibits HaCaT cells from synthesizing interleukin-6 (IL-6), a pro-inflammatory cytokine associated with cutaneous inflammation, in response to UVB radiation. These results suggest that the 12-HHT/BLT2 axis can act to suppress inflammation by promoting the orderly death of damaged cells and blocking IL-6 production. Opposition between the pro-inflammatory LTB4/BLT1 and anti-inflammatory actions of the 12-HHT/BLT2 axes occurs in another setting. In a mice model of ovalbumin-induced allergic airway disease, 12-HHT and its companion cyclooxygenase metabolites, Prostaglandin E2 and Prostaglandin D2, but not 12 other lipoxygenase or cycloxygenase metabolites, showed a statistically significantly increase in bronchoalveolar lavage fluid levels after intratracheal ovalbumin challenge; after this challenge, only 12-HHT, among the monitored BLT2 receptor-activating ligands (LTB4, the 12(S) stereoisomer of 12-HETE, and 15(S)-HETE) attained levels capable of activating BLT2 receptors. Also, BLT2 knockout mice exhibited a greatly enhanced response to ovalbumin challenge. Finally, BLT2 receptor expression was significantly reduced in allergy-regulating CD4+ T cells from patients with asthma compared to healthy control subjects. Unlike LTB4 and its BLT1 receptor, which are implicated in contributing to allergen-based airway disease in mice and humans, 12-HHT and its BLT2 receptor appear to suppress this disease in mice and may do so in humans. While further studies to probe the role of the 12-HHT/BLT2 axis in human inflammatory and allergic diseases, the current studies indicate that 12-HHT, acting through BLT2, may serve to promote or limit, inflammatory and to promote allergic responses.
