Background: Viral infections are key for acute exacerbation in chronic lung diseases (CLD). Interleukin-6 (IL-6) is produced by bronchial epithelial cells (BEC) after viral infections and central for severity and post COVID syndrome (PCS). While asthma does not lead to more severe COVID, a higher risk for PCS is suggested. However, regulation of IL-6 during viral infections in asthma is only partially understood.

Objective: We hypothesize that IL-6 gene regulation is transcriptionally augmented in BEC after viral analog stimulation in a pro-allergic environment.

Methods: Primary BEC were differentiated (21 days, air liquid interface) and stimulated with recombinant human IL-13, Poly (I:C) (PIC) or both. On day 28 gene expression was analyzed (Agilent, USA). ENCODE data was used to identify transcription factors (TFs) for the IL-6 promoter. Chromatin immunoprecipitation (ChIP) of PR domain zinc finger protein 1 (PRDM1; clone 9115BF) and of Interferon regulatory factor 1 (IRF1; clone ab240299) was conducted.

Results: IL-6 models revealed a strong association with two TFs (IFR1: p<0.001, r2=0.85; PRDM1: p<0.001, r2=0.86, verified by ChIP). Combined stimulation with IL-13 & PIC significantly augmented PRDM1 and IRF1 expression (PIC & IL-13 vs PIC: PRDM1: p<10-6; IRF1: p<10-7) (PIC & IL-13 vs IL-13: PRDM1: p<10-6; IRF1: p<10-7).

Conclusion: There was significant binding of both TFs in IL-6. IL-13 exposure significantly augmented IL-6 expression in BEC. This could suggest that pro-allergic inflammation fosters higher IL-6 responses in BEC, with potential relevance for post COVID sequelae. Further studies of the interaction between respiratory virus and CLD are needed.