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Substance P and IL-33 administered together stimulate a marked secretion of IL-1β from human mast cells, inhibited by methoxyluteolin

Alexandra Taracanova,I. Tsilioni,P. Conti,E. Norwitz,S. Leeman,T. Theoharides

Published 2018 in Proceedings of the National Academy of Sciences of the United States of America

ABSTRACT

Significance Mast cells are mandatory for allergic reactions and participate in inflammatory responses in which the peptide substance P (SP) and the cytokine IL-33 are involved. This report shows that SP administered together with IL-33 to cultured human mast cells causes a marked increase in the secretion and gene expression of IL-1β. These responses are mediated via the activation of the SP receptor NK-1 and the IL-33 receptor ST2 and can be inhibited by the natural flavonoid methoxyluteolin. These findings highlight the important role of SP and IL-33 in mast cell secretion of IL-1β and point to targets for the development of therapies for inflammatory diseases. Mast cells are critical for allergic and inflammatory responses in which the peptide substance P (SP) and the cytokine IL-33 are involved. SP (0.01–1 μM) administered together with IL-33 (30 ng/mL) to human cultured LAD2 mast cells stimulates a marked increase (P < 0.0001) in secretion of the proinflammatory cytokine IL-1β. Preincubation of LAD2 (30 min) with the SP receptor (NK-1) antagonists L-733,060 (10 μM) or CP-96345 (10 µM) inhibits (P < 0.001) secretion of IL-1β stimulated by either SP (1 μM) or SP together with IL-33 (30 ng/mL). Surprisingly, secretion of IL-1β stimulated by IL-33 is inhibited (P < 0.001) by each NK-1 antagonist. Preincubation with an antibody against the IL-33 receptor ST2 inhibits (P < 0.0001) secretion of IL-1β stimulated either by IL-33 or together with SP. The combination of SP (1 μM) with IL-33 (30 ng/mL) increases IL-1β gene expression by 90-fold in LAD2 cells and by 200-fold in primary cultured mast cells from human umbilical cord blood. The combination of SP and IL-33 increases intracellular levels of IL-1β in LAD2 by 100-fold and gene expression of IL-1β and procaspase-1 by fivefold and pro-IL-1β by twofold. Active caspase-1 is present even in unstimulated cells and is detected extracellularly. Preincubation of LAD2 cells with the natural flavonoid methoxyluteolin (1–100 mM) inhibits (P < 0.0001) secretion and gene expression of IL-1β, procaspase-1, and pro-IL-1β. Mast cell secretion of IL-1β in response to SP and IL-33 reveals targets for the development of antiinflammatory therapies.

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