Fungal zymosan induces leukotriene production by human mast cells through a dectin-1-dependent mechanism

Background: Fungi are capable of causing or exacerbating inflammatory disease in the airways. We have previously demonstrated that zymosan and peptidoglycan induce the production of cysteinyl leukotrienes from human mast cells. However, the mechanisms of pathogen-induced leukotriene production by immune effector cells are very poorly understood. The coreceptor dectin-1, through a Syk tyrosine kinase-dependent pathway, can mediate some responses to fungal challenge, but its expression by mast cells and its involvement in lipid mediator responses have not been assessed. Objective: In the current study, the potential role of dectin-1 in zymosan-induced leukotriene production from human mast cells was examined. Methods: Human mast cells were examined for dectin-1 mRNA and protein expression. Human mast cells were incubated with either zymosan or peptidoglycan in the presence or absence of specific inhibitors for dectin-1 or Syk tyrosine kinase and mediator production examined. Results: Human mast cells were found to express a functional isoform of dectin-1. Both peptidoglycan and zymosan induced significant amounts of leukotriene (LT)-B ₄ and LTC ₄. The dectin-1 inhibitors laminarin and glucan phosphate reduced the LTC ₄ response to zymosan by more than 60% but did not alter peptidoglycan responses. Inhibitors of Syk tyrosine kinase activity significantly decreased LTC ₄ production in response to both peptidoglycan and zymosan. Conclusion: These data demonstrate mast cell expression of the coreceptor dectin-1 and a role for this molecule in the generation of cysteinyl leukotrienes. Clinical implications: These findings suggest new approaches to the selective inhibition of lipid mediator production in response to fungal infection or exposure.