BAFF can also bind to BAFF-R.20There were increased transcript levels of TACI (Fig 6,C) and BCMA (Fig 6,D) receptors in the lungs of 12/15-LO/mice. the 2 2 models. == Results == In the mucosal model RPB8 12/15-LO knockout mice were protected from the development of allergic sensitization and airways inflammation, as evidenced by circulating levels of allergen-specific IgE, IgG1, and IgG2a; the profile of inflammatory cells in bronchoalveolar lavage fluid; and the expression of cytokines and mediators in lung tissue. In the systemic model 12/15-LO knockout mice were not protected. This suggested the presence of a lung-restricted protective role for 12/15-LO deficiency that was potentially accounted for by increased activation of mucosal B cells and increased production of the known mucosal-specific protective mediator secretory IgA. == Conclusions == Induction of 15-LO-1 in asthma might contribute to allergic sensitization and airways inflammation, potentially by causing suppression of secretory IgA. Keywords:Asthma, allergy, inflammation, lipoxygenase, IL-13, IgA, B cells, airway, lung Allergen exposures at the airway mucosal surface are well tolerated by most individuals but often trigger asthma exacerbations.1This suggests a disease-related failure of first-line airway mucosal defenses, which might help to explain the high levels of circulating antigen-specific IgE that often develop in asthmatic subjects after aeroallergen exposures.2One critical first-line mucosal defense is mediated by IgA produced by plasma cells underlying mucosal surfaces.3The locally produced IgA is transported by the polymeric immunoglobulin receptor (pIgR) onto mucosal surfaces as secretory IgA (SIgA).4SIgA is a noninflammatory protective mediator that functions through a spectrum of low-affinity and high-affinity interactions with allergens, toxins, and microbes and by binding to specific receptors on host cells.3Decreases of SIgA levels in bronchoalveolar lavage fluid (BALF) from subjects with asthma correlate with worsening symptoms.5Therefore suppression of SIgA could result in failure of a first-line mucosal immune defense in patients with asthma. In previous studies 12/15-lipoxygenase (12/15-LO) was identified as an allergen- and IL-13induced gene in the lungs of mice.6Its human ortholog (15-LO-1) is highly expressed in the airways of subjects with severe asthma.7The 15-LO-1 and 12/15-LO Melanotan II enzymes insert molecular oxygen into arachidonic acid (AA), resulting in formation of 12(S)-hydroxyeicosatetraenoic acid [12(S)-HETE] and 15(S)-HETE.8The hypothesis was tested that 12/15-LO contributes to the severity of allergic inflammation by comparing allergen-induced systemic antibody responses and inflammatory responses in the lungs of wild-type and 12/15-LO knockout mice that were exposed to allergen either by means of intraperitoneal injection or by means of repeated airways exposure. The approach was used to identify systemic and mucosal-specific Melanotan II functions of 12/15-LO. The results point to 12/15-LO as a mucosal-specific inhibitor of SIgA and a contributor to the development of allergic sensitization and airways inflammation in mice. == METHODS == == Mice == The experiments were approved by the Northwestern University Animal Care and Use Committee and complied with the Guide for the care and use of laboratory animals prepared by the Institute of Laboratory Animal Resources, National Research Council, and published by the National Academy Press (revised 1996). 12/15-LO/and strain-matched wild-type mice (Jackson Laboratories, Bar Harbor, Me) were interbred to generate in-house C57Bl/6 wild-type and 12/15-LO/littermates. AKR/J, C57Bl/6, BALB/c, Melanotan II and 129/SvJ mice and BALB/c wild-type and signal transducer and activator of transcription 6 (STAT6)deficient mice were also evaluated. == Protocols == Mice were sensitized by means of intraperitoneal injection of 10 g of grade Vovalbumin in 200L of PBS with adjuvant (alum) twice, 1 week apart, or an equivalent volume of PBS with alum alone (control animals). A small volume of blood was collected from behind the eye immediately before each injection. One week after the second intraperitoneal injection, a different set of mice also received a total of 2 airway challenges, 1 day apart, with 1.5% ovalbumin in 50 L of PBS or an equivalent volume of PBS (control animals) through the intratracheal route and were harvested 2 days later. A different group of mice received 1.5% ovalbumin (50 L of PBS) through the intratracheal route once every 4 days or an equivalent volume of PBS (control animals) for a total of 4 airway challenges. A small sample of blood was collected from these mice immediately before the second or third airway challenge. Mice were harvested 2 days after the.