| First Author | McGuire VA | Year | 2017 |
| Journal | Mol Cell Biol | Volume | 37 |
| Issue | 1 | PubMed ID | 27795299 |
| Mgi Jnum | J:242992 | Mgi Id | MGI:5907400 |
| Doi | 10.1128/MCB.00454-16 | Citation | McGuire VA, et al. (2017) Beta Interferon Production Is Regulated by p38 Mitogen-Activated Protein Kinase in Macrophages via both MSK1/2- and Tristetraprolin-Dependent Pathways. Mol Cell Biol 37(1) |
| abstractText | Autocrine or paracrine signaling by beta interferon (IFN-beta) is essential for many of the responses of macrophages to pathogen-associated molecular patterns. This feedback loop contributes to pathological responses to infectious agents and is therefore tightly regulated. We demonstrate here that macrophage expression of IFN-beta is negatively regulated by mitogen- and stress-activated kinases 1 and 2 (MSK1/2). Lipopolysaccharide (LPS)-induced expression of IFN-beta was elevated in both MSK1/2 knockout mice and macrophages. Although MSK1 and -2 promote the expression of the anti-inflammatory cytokine interleukin 10, it did not strongly contribute to the ability of MSKs to regulate IFN-beta expression. Instead, MSK1 and -2 inhibit IFN-beta expression via the induction of dual-specificity phosphatase 1 (DUSP1), which dephosphorylates and inactivates the mitogen-activated protein kinases p38 and Jun N-terminal protein kinase (JNK). Prolonged LPS-induced activation of p38 and JNK, phosphorylation of downstream transcription factors, and overexpression of IFN-beta mRNA and protein were similar in MSK1/2 and DUSP1 knockout macrophages. Two distinct mechanisms were implicated in the overexpression of IFN-beta: first, JNK-mediated activation of c-jun, which binds to the IFN-beta promoter, and second, p38-mediated inactivation of the mRNA-destabilizing factor tristetraprolin, which we show is able to target the IFN-beta mRNA. |
