Influenza A viruses (IAVs) are negative-sense, single-stranded, segmented RNA viruses, which primarily targets respiratory epithelial cells and produces clinical outcomes ranging from mild upper respiratory infection to severe pneumonia. MicroRNAs (miRNAs) represent a family of small noncoding RNAs controlling translation and transcription of many genes. The human miR-29 family of miRNAs has three mature members, miR-29a, miR-29b, and miR-29c. Recent studies have revealed that miR-29 is involved in regulation of the innate and adaptive immune responses. However, the function of miR-29 in the immune response to IAV infection remains to be further explored. Our previous study has shown that miR-29 family members are up-regulated during IAV infection, especially miR-29c. Here we report that miR-29c is involved in inhibition of IAV-induced innate immune responses. We found that posttranscriptional regulation was involved in IAV-induced A20 expression in A549 cells. Consistent with a previous report, miR-29c functionally protected A20 transcripts in A549 cells. Overexpression of miR-29c with miR-29c mimic enhanced IAV-induced A20 protein expression and conversely that miR-29c inhibitor significantly blocked IAV-induced A20 protein expression in A549 cells. Furthermore, functional results showed that IAV-induced miR-29c expression correlated with decreased NF-kappa B activity and expression of several antiviral and proinflammatory cytokines via up-regulation of A20. Together, the findings indicate a new role of miR-29c in IAV infection and suggest its induction may contribute to counteract the innate immune response. (C) 2014 Elsevier Inc. All rights reserved.