Methods: C57BL/6 females received six intranasal applications of DEP or PBS. Two weeks after the final application females were mated. Offspring were immunized and challenged with ovalbumin (OVA) or received PBS. Offspring lungs were examined for levels of mRNA for cytokines of type-2 immunity (IL-5, IL-13), IL-17 family (IL-17A, IL-17F), IL-1 family (IL-1β, IL-1α, IL-33), IL-6 and TNFα. Cytokine-depleted (antibody) and control pups were examined for features of asthma.
Results: Pre-pregnancy exposure to DEP induced transcripts for IL-1β, IL-5, IL-6, IL-13 and IL-17A as found by comparing PBS-treated pups of DEP-exposed mothers (DEP-PBS pups) with PBS-treated pups of PBS-exposed mothers (PBS-PBS pups). Ovalbumin synergized with DEP in transcription of IL-1β. Compared to PBS-OVA pups, DEP-OVA pups had more IL-1β and IL-17A. Other master regulatory cytokines of the IL-1 family– IL-1α and IL-33 were not affected by DEP. Depletion of IL-1β in DEP-OVA pups significantly reduced peribronchial inflammation (histology) and BAL eosinophil counts and completely blocked airway hyperresponsiveness (AHR) to methacholine (FlexiVent). IL-1β depletion also led to a reduction in IL-17A. IL-17A depletion prevented AHR but had no effect on eosinophils or peribronchial inflammation.
Conclusions: Pre-pregnancy exposure to DEP has a priming effect on pulmonary immunity in offspring through induction of cytokines belonging to multiple immune response pathways. IL-1β, an upstream master regulatory cytokine drives predisposition to asthma. IL-1β regulates AHR through IL-17A.