TY - JOUR T1 - S100 proteins induce MUC5AC production in airway epithelial cells JF - European Respiratory Journal JO - Eur Respir J VL - 44 IS - Suppl 58 SP - P3887 AU - Jin Hyun Kang AU - Sae Mi Hwang AU - Il Yup Chung Y1 - 2014/09/01 UR - http://erj.ersjournals.com/content/44/Suppl_58/P3887.abstract N2 - S100A8, S100A9, and S100A12 are damage-associated molecular pattern (DAMP) molecules that are mainly released by neutrophils. They initiate and modulate local inflammation and innate immune responses. Airway mucus hyperproduction is a paramount feature of chronic airway obstructive diseases such as severe asthma, chronic obstructive pulmonary disease, and cystic fibrosis, which are closely associated with neutrophilic airway inflammation. In the present study, we report a new role for S100A8, S100A9, and S100A12 for producing MUC5AC, a major mucin protein in the respiratory tract. All three S100 proteins induced MUC5AC mRNA and protein expression in normal human bronchial epithelial (NHBE) cells as well as NCI-H292 cells. A TLR4 inhibitor almost completely abolished MUC5AC expression by all the three S100 proteins, while neutralization of the receptor for advanced glycation end-products (RAGE) inhibited only S100A12-mediated production of MUC5AC. Treatment with various pharmacological inhibitors showed that MUC5AC production by these three S100 proteins was achieved through activation of multiple signaling molecules, including MAPKs and NF-κB. Biochemical analyses demonstrated that S100A8, S100A9, and S100A12 equally elicited both phosphorylation of ERK and nuclear translocation of NF-κB/degradation of cytosolic IκB with similar kinetics through TLR4. In contrast, S100A12 preferentially activated the ERK pathway rather than the NF-κB pathway through RAGE. Collectively, our results suggest that S100A8 S100A9, and S100A12 all serve as key mediators linking neutrophil-dominant airway inflammation to mucin hyperproduction, thereby contributing to the pathophysiology of obstructive airway diseases. ER -