MSK1 regulates the transcription of IL-1ra in response to TLR activation in macrophages

Abstract

The activity of the pro-inflammatory cytokine IL (interleukin)-1 is closely regulated in vivo via a variety of mechanisms, including both the control of IL-1 production and secretion as well as naturally occurring inhibitors of IL-1 function, such as IL-1ra (IL-1 receptor antagonist). IL-1ra is homologous with IL-1, and is able to bind but not activate the IL-1 receptor. IL-1ra can be produced by a variety of cell types, and its production is stimulated by inflammatory signals. In the present study, we show that in macrophages the TLR (Toll-like receptor)-mediated induction of IL-1ra from both its proximal and distal promoters involves the p38 and ERK1/2 (extracellular-signal-regulated kinase 1/2) MAPK (mitogen-activated protein kinase) cascades. In addition, we show that MSK1 and 2 (mitogen- and stress-activated kinase 1 and 2), kinases activated by either ERK1/2 or p38 in vivo, are required for the induction of both IL-1ra mRNA and protein. MSKs regulate IL-1ra transcription via both IL-10-dependent and -independent mechanisms in cells. Consistent with this, knockout of MSK in mice was found to result in a decrease in IL-1ra production following LPS (lipopolysaccharide) injection. MSKs therefore act as important negative regulators of inflammation following TLR activation.

PGE2 Induces Macrophage IL-10 Production and a Regulatory-like Phenotype via a Protein Kinase A–SIK–CRTC3 Pathway

“…Primary bone marrow-derived macrophages (BMDMs) were isolated as described previously (33). Briefly, to obtain BMDMs, bone marrow cells were maintained on bacterial grade plates for 1 wk in DMEM supplemented with 10% heat-inactivated FBS (Biosera), 2 mM L-glutamine, 100 U/ml penicillin G, 100 mg/ml streptomycin, 0.25 mg/ml amphotericin (Invitrogen), and 5 ng/ml mCSF (R&D Systems).…”

“…Equal amounts of soluble protein from each condition were reduced, alkylated and digested with trypsin. Phospho-peptides were then enriched by sequential hydrophilic chromatography followed by Fe 3+ -immobilized metal affinity chromatography (33). Phospho-peptides were measured by tandem mass spectroscopy on Thermo Fisher Scientific LTQ Orbitrap Velos instrument set to perform top-15 data-dependent collisioninduced dissociation analysis in the 350-1600 m/z range using a resolution of 60,000 for the precursor scan and a minimal intensity for sequencing of 10,000 counts.…”

Glatiramer acetate triggers PI3Kδ/Akt and MEK/ERK pathways to induce IL-1 receptor antagonist in human monocytes

“…In monocytes activated under acute/infectious or chronic/sterile inflammatory conditions, the production of sIL1Ra depends on the activation of PI3Kδ (33), highlighting an important role of this kinase independently of the stimulus. In addition, both MAPK and glycogen-synthase kinase 3 (GSK3) were shown to play a part in the control of sIL-1Ra production (34,35). Here, we address the question of GA-induced signaling pathways that lead to sIL-1Ra production in monocytes.…”

MSK1 and MSK2 Inhibit Lipopolysaccharide-Induced Prostaglandin Production via an Interleukin-10 Feedback Loop

“…In line with this, in response to LPS, MSK-deficient macrophages secrete elevated levels of TNF, interleukin 6 (IL-6), and IL-12 compared to wild-type cells. In response to LPS, the secretion of the anti-inflammatory cytokines IL-10 and IL-1ra, as well as induction of the phosphatase DUSP1 (mkp1), which limits p38 and c-Jun N-terminal kinase (JNK) activation, was significantly reduced by the knockout of MSK1 and MSK2 (21,29,30). The ability of MSKs to regulate IL-10 and dual-specificity phosphatase (DUSP) gene transcription in response to LPS in macrophages reflects a role for MSK-mediated CREB phosphorylation in the transcription of these genes (21,31).…”