MAIL Regulates Human Monocyte IL-6 Production

Abstract

IL-6 is a pleiotropic cytokine implicated in the pathogenesis of disorders such as sepsis and cancer. We noted that human monocytes are excellent producers of IL-6 as compared with monocyte-derived macrophages. Because macrophages from molecule containing ankyrin repeats induced by LPS (MAIL) knockout animals have suppressed IL-6 production, we hypothesized that regulation of MAIL is key to IL-6 production in humans and may explain the differences between human monocytes and macrophages. To test this hypothesis fresh human monocytes and monocyte-derived macrophages were compared for MAIL expression in response to LPS. LPS-induced monocyte MAIL expression was highly inducible and transient. Importantly for our hypothesis MAIL protein expression was suppressed during differentiation of monocytes to macrophages. Of note, the human MAIL protein detected was the 80 kDa MAIL-L form and human MAIL showed nuclear localization. Human MAIL-L bound to p50 subunit of the NF-κB and increased IL-6 luciferase promoter activity in a cEBPβ, NF-κB, and AP-1-dependent fashion. Like the differences in MAIL induction, monocytes produced 6-fold more IL-6 compared with macrophages (81.7 ± 29.7 vs 12.6 ± 6.8 ng/ml). Furthermore, suppression of MAIL by small interfering RNA decreased the production of IL-6 significantly in both THP-1 cells and in primary monocytes. Costimulation of monocytes with LPS and muramyl dipeptide induced an enhanced IL-6 response that was suppressed by siMAIL. Our data suggests that MAIL is a key regulator of IL-6 production in human monocytes and plays an important role in both TLR and NOD-like receptor ligand induced inflammation.

House Dust Mite Allergens and the Induction of Monocyte Interleukin 1β Production That Triggers an IκBζ-Dependent Granulocyte Macrophage Colony-Stimulating Factor Release from Human Lung Epithelial Cells

“…Notably, at the protein level, IkBz-L is the predominantly expressed isoform in lung epithelial cells. This preferential expression of IkBz-L over IkBz-S is consistent with previous publications from our group and others (21,26,34). To our knowledge, we are the first to demonstrate a role for IkBz in mediating inflammation associated with house dust mite-induced asthma.…”

“…Although there have been studies suggesting that IkBz inhibits NF-kB activity (22,23), the predominant function of IkBz is believed to be transcriptional activation of secondary response genes through NF-kB binding (21,27,33). In this report, we propose a model for house dust mite-induced asthma ( Figure 7F) in which IkBz plays a critical role in regulating inflammatory responses in the lung epithelium.…”

“…NFKBIZ is a primary response gene, induced rapidly in monocytes and macrophages in response to LPS, which encodes the transcription factor IkBz, also called MAIL or INAP (19)(20)(21)(22). The molecule belongs to the IkB family due to the presence of multiple ankyrin repeat sequences at its carboxy terminus, with the help of which it binds to the subunits of nuclear factor kB (NF-kB) (19,22).…”

p16INK4a Exerts an Anti-Inflammatory Effect through Accelerated IRAK1 Degradation in Macrophages

“…IL-6 expression in monocytes/macrophages depends on NF-kB and AP-1 pathways because loss of either pathway severely impaired IL-6 expression (34,35). In contrast, TNF-a expression in monocytes/macrophages depends primarily on NF-kB because mutation of the AP-1 binding site in the TNF-a promoter sequence did not alter its expression (36).…”

IκBζ is a regulator for the senescence-associated secretory phenotype in DNA damage- and oncogene-induced senescence

“…IkBf has previously been identified as an important regulator of IL6 expression in the Toll-like receptor/IL1 receptor pathway (Yamamoto et al, 2004;Seshadri et al, 2009). To investigate a functional role of IkBf for SASP formation, we transfected MCF7/ Ras G12V cells with an siRNA targeting IkBf.…”