Loss of ZIP8 Represses Interleukin-6 Expression in A549 Cells

Abstract

Zrt-/Irt-like protein 8 (ZIP8) is a recently identified divalent metal cation transporter expressed ubiquitously throughout the body. Tissue distribution profiles have indicated that ZIP8 is highly expressed in the lungs. Previous literature has reported diverse functions for ZIP8 in the immune system, particularly in regulating host defense and alveolar epithelial renewal. Here, we first show that ZIP8 is expressed in alveolar epithelial cells but not detected in pulmonary endothelial cells. We then utilized a ZIP8 knockout (KO) type II pneumocyte model to study the link between ZIP8 and interleukin-6 (IL6). We show that the loss of ZIP8 causes severe repression of IL6 mRNA and protein expression, which was recovered following the reintroduction of ZIP8 expression. The loss of another ZIP family metal transporter, ZIP14, did not have the same effect, highlighting a specific role for ZIP8 in regulating IL6 expression. Finally, we show that the loss of ZIP8 represses IL6 pre-mRNA expression which suggests a transcriptional level of regulation, identifying a potential mechanism by which ZIP8 influences IL6 expression. Together, this work identifies ZIP8 as a novel regulator of IL6 expression in alveolar epithelial cells.