MicroRNA-155 Regulates Inflammatory Cytokine Production in Tumor-associated Macrophages via Targeting C/EBPβ

Macrophages (M phi) are prominent components of solid tumors and exhibit distinct phenotypes in different microenvironments. We have recently found that tumors can alter the normal developmental process of M phi to trigger transient activation of monocytes, but the underlying regulatory mechanisms are incompletely understood. Here, we showed that the protein expression of transcription factor C/EBP beta was markedly elevated in tumor-associated M phi both in vitro and human tumors in situ. The expression of C/EBP beta protein correlated with cytokine production in tumor-activated monocytes. Moreover, we found that C/EBP beta expression was regulated at the post-transcriptional level and correlated with sustained reduction of microRNA-155 (miR-155) in tumor-activated monocytes. Bioinformatic analysis revealed that C/EBP beta is a potential target of miR-155 and luciferase assay confirmed that C/EBP beta translation is suppressed by miR-155 through interaction with the 3'UTR of C/EBP beta mRNA. Further analysis showed that induction of miR-155 suppressed C/EBP beta protein expression as well as cytokine production in tumor-activated monocytes, an effect which could be mimicked by silencing of C/EBP beta. These results indicate that tumor environment causes a sustained reduction of miR-155 in monocytes/M phi which in turn regulates the functional activities of monocytes/M phi by releasing the translational inhibition of transcription factor C/EBP beta. Cellular & Molecular Immunology. 2009;6(5):343-352.