Leukotriene D4 and prostaglandin E2 signals synergize and potentiate vascular inflammation in a mast cell–dependent manner through cysteinyl leukotriene.

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Leukotriene D4 and prostaglandin E2 signals synergize and potentiate vascular inflammation in a mast cell–dependent manner through cysteinyl leukotriene receptor 1 and E-prostanoid receptor 3 Vinay Kondeti, PhD, Nosayba Al-Azzam, MS, Ernest Duah, MS, Charles K. Thodeti, PhD, Joshua A. Boyce, MD, Sailaja Paruchuri, PhD Journal of Allergy and Clinical Immunology Volume 137, Issue 1, Pages 289-298 (January 2016) DOI: 10.1016/j.jaci.2015.06.030 Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 Effect of LTD4 and PGE2 on ear edema in mice in vivo and MC activation in vitro. Wild-type (WT) BALB/c mice were treated with saline (Sal), 0.5 μmol/L LTD4, 0.5 μmol/L PGE2, or LTD4 plus PGE2. A, Ear thickness. B, Hematoxylin and eosin staining and toluidine blue staining. C, Quantification (blind analysis) of MCs per millimeter. D, Ear thickness in C57BL/6 and W-sh mice treated with 0.5 μmol/L LTD4, PGE2, and LTD4 plus PGE2. Results are means ± SEMs from 4 to 6 mice per group per experiment and 3 experiments performed. E-I, LAD2 cells (Fig 1, E-H) and hMCs (Fig 1, I) were stimulated with 0.5 μmol/L LTD4, 0.5 μmol/L PGE2, or both, and calcium flux (Fig 1, E and F), c-fos (Fig 1, G and I), and MIP-1β (Fig 1, H) were analyzed. *P < .05, **P < .01, and ***P < .001. Journal of Allergy and Clinical Immunology 2016 137, 289-298DOI: (10.1016/j.jaci.2015.06.030) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 LTD4-primed and PGE2-mediated calcium, c-fos, and MIP-1β responses in MCs are partly sensitive to CysLT1R inhibition. LAD2 cells were stimulated with 0.5 μmol/L LTD4, 0.5 μmol/L PGE2, or both in the presence or absence of MK571 (1 μmol/L) and BayCysLT2 (1 μmol/L), and calcium flux (A), c-fos (B and C), and MIP-1β (D) were analyzed. *P < .05 and ***P < .001. Journal of Allergy and Clinical Immunology 2016 137, 289-298DOI: (10.1016/j.jaci.2015.06.030) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 EP3 relays synergistic activation of c-fos and MIP-1β in response to PGE2 and LTD4. LAD2 cells were treated with LTD4 (0.5 μmol/L) ± PGE2 (0.5 μmol/L) or iloprost (10 μmol/L), butaprost (5 μmol/L), or sulprostone (100 nmol/L) ± L-798 (100 nmol/L), and c-fos (A, B, D, and E) and MIP-1β (C and F) were analyzed. *P < .05, **P < .01, and ***P < .001. Journal of Allergy and Clinical Immunology 2016 137, 289-298DOI: (10.1016/j.jaci.2015.06.030) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 4 Combined effect of CysLT1R antagonist and EP3 antagonist on synergistic responses to LTD4 and PGE2. LAD2 cells (A-C) and hMCs (D and E) were preincubated with MK571 (1 μmol/L) and L-798 (100 nmol/L) separately or in combination and treated with LTD4 (0.5 μmol/L) ± PGE2 (0.5 μmol/L), and c-fos (Fig 4, A, B, D, and E) and MIP-1β (Fig 4, C) were analyzed. *P < .05, **P < .01, and ***P < .001. Journal of Allergy and Clinical Immunology 2016 137, 289-298DOI: (10.1016/j.jaci.2015.06.030) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 5 Inflammatory gene induction and COX-2 protein by LTD4 and PGE2 in LAD2 cells. LAD2 cells were stimulated with 0.5 μmol/L LTD4, PGE2, or both; transcript levels of MIP-1β, TNF-α, IL-8, COX-2, and COX-1 were analyzed by means of real-time PCR at 2 hours of stimulation (A-E); and COX-2 protein levels were determined (F) in cell lysates. *P < .05, **P < .01, and ***P < .001. Journal of Allergy and Clinical Immunology 2016 137, 289-298DOI: (10.1016/j.jaci.2015.06.030) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 6 LTD4 and PGE2 crosstalk causes a synergistic increase in PGD2 secretion and Erk phosphorylation and is mediated through PKG and Erk. LAD2 cells were stimulated with 0.5 μmol/L LTD4, 0.5 μmol/L PGE2, or both in the presence or absence of MK571 (1 μmol/L), L-798 (100 nmol/L), KT5823 (KT; 5 μmol/L), or PD98059 (PD; 50 μmol/L) before treatment, and PGD2 secretion (A and F), Erk phosphorylation (B), c-fos (C and D), and MIP-1β generation (E) were analyzed. *P < .05, **P < .01, and ***P < .001. Journal of Allergy and Clinical Immunology 2016 137, 289-298DOI: (10.1016/j.jaci.2015.06.030) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 7 Simultaneous inhibition of CysLT1R and EP3 on LTD4 plus PGE2–mediated MC activation in vitro and ear edema in vivo. CysLT1R, EP3, or both and PKG were knocked down in LAD2 cells by corresponding siRNAs (10 nmol/L), and c-fos (A and B) and MIP-1β (C) were analyzed with LTD4 plus PGE2 treatment. D, Ear thickness in BALB/c mice treated with 0.5 μmol/L LTD4 plus PGE2 ± MK571 (1 μmol/L) or L-798 (100 nmol/L). Results in Fig 7, D, are means ± SEMs from 4 to 6 mice per group per experiment and 3 experiments performed. *P < .05, **P < .01, and ***P < .001. Journal of Allergy and Clinical Immunology 2016 137, 289-298DOI: (10.1016/j.jaci.2015.06.030) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions