title: MicroRNA-125b modulates inflammatory chemokine CCL4 expression in immune cells and its reduction causes CCL4 increase with age.
abstract: Chemokines play a pivotal role in regulating the immune response through a tightly controlled expression. Elevated levels of inflammatory chemokines commonly occur with aging but the mechanism underlying this age-associated change is not fully understood. Here, we report the role of microRNA-125b (miR-125b) in regulating inflammatory CC chemokine 4 (CCL4) expression in human immune cells and its altered expression with aging. We first analyzed the mRNA level of CCL4 in eight different types of immune cells including CD4 and CD8 T-cell subsets (naïve, central and effector memory), B cells and monocytes in blood from both young (≤42 years) and old (≥70 years) adults. We observed that monocytes and naïve CD8 T cells expressed higher levels of CCL4 and exhibited an age-related increase in CCL4. We then found the level of miR-125b was inversely correlated with the level of CCL4 in these cells, and the level of miR-125b was reduced in monocytes and naïve CD8 T cells of the old compared to the young adults. Knock-down of miR-125b by shRNA in monocytes and naïve CD8 T cells led to an increase of CCL4 protein, whereas enhanced miR-125b expression by transfection in naïve CD8 T cells resulted in a reduction of the CCL4 mRNA and protein in response to stimulation. Finally, we demonstrated that miR-125b action requires the 'seed' sequence in 3'UTR of CCL4. Together these findings demonstrated that miR-125b is a negative regulator of CCL4 and its reduction is partially responsible for the age-related increase of CCL4.
authors.affiliation: Laboratory of Molecular Biology & Immunology, National Institute on Aging, National Institutes of Health, 251 Bayview Blvd., Baltimore, MD, 21224, USA.
authors.forename: Nai-Lin
authors.initials: NL
authors.lastname: Cheng
authors.forename: Xiaochun
authors.initials: X
authors.lastname: Chen
authors.forename: Jiewan
authors.initials: J
authors.lastname: Kim
authors.forename: Alvin H
authors.initials: AH
authors.lastname: Shi
authors.forename: Cuong
authors.initials: C
authors.lastname: Nguyen
authors.forename: Robert
authors.initials: R
authors.lastname: Wersto
authors.forename: Nan-Ping
authors.initials: NP
authors.lastname: Weng
mesh_terms: D020413:3' Untranslated Regions; D000367:Age Factors; D000368:Aged; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D016922:Cellular Senescence / Q000276:immunology*; D054407:Chemokine CCL4 / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology; D006801:Humans; D008213:Lymphocyte Activation; D035683:MicroRNAs / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D009000:Monocytes / Q000276:immunology*
chemical_list: D020413:3' Untranslated Regions; C066507:CCL4 protein, human; D054407:Chemokine CCL4; C531888:MIRN125 microRNA, human; D035683:MicroRNAs
keywords: CCL4; aging; and naïve CD8 T cell; immune cells; miR-125b; monocyte