MKP-1 negatively regulates LPS-mediated IL-1β production through p38 activation and HIF-1α expression

Abstract

Interleukin 1 beta (IL-1β) is a pro-inflammatory cytokine that plays a major role in inflammatory diseases as well as cancer. The inflammatory response after Toll-like receptor (TLR) 4 activation is tightly regulated through phosphorylation of MAP kinases, including p38 and JNK pathways. The activation of MAP kinases is negatively regulated by MAPK phosphatases (MKPs). MKP-1 preferentially dephosphorylates p38 and JNK. IL-1β is regulated through the activation of MAPK, including p38 as well as several transcription factors. The oxygen-sensitive transcription factor HIF-1α is a known transcription factor for several inflammatory cytokines including IL-1β and IL-6. Here, we report that MKP-1 regulates HIF-1α expression in response to LPS. MKP-1 deficient bone marrow derived macrophages (BMDMs) exhibited increased reactive oxygen species (ROS) production and higher HIF-1α expression. In contrast, the expression of all three isoforms of prolyl hydroxylases (PHDs), which are important in destabilizing HIF-1α through hydroxylation, were significantly decreased in MKP-1 deficient BMDMs. LPS challenge of MKP-1 deficient BMDMs led to a substantial increase in IL-1β production. An inhibitor of HIF-1α significantly decreased LPS mediated IL-1β production both at the transcript and protein levels. Similarly, inhibition of p38 MAP kinase reduced LPS mediated pro-IL-1β and HIF-1α protein levels as well as ROS production in MKP-1 deficient BMDMs. These findings demonstrate a regulatory function for MKP-1 in modulating IL-1β expression through p38 activation, ROS production and HIF-1α expression.

The dataset describes: HIF-1 α expression and LPS mediated cytokine production in MKP-1 deficient bone marrow derived murine macrophages

“…This dataset extends the reproducibility of the recent published data [1]. BMDMs derived from WT and MKP-1 -/- mice exhibit higher p38 and JNK activation in response to LPS (Fig.…”

Comparison of Inflammatory Effects in THP-1 Monocytes and Macrophages after Exposure to Metal Ions

“…It cannot be ruled out that the artificial situation in cell culture, e.g., the attachment to the cell culture dish or the differentiation with Phorbol-12-myristat-13-acetat, provided enough stimulus for IL-1β secretion. Danger signaling might not be the only mechanisms involved in IL-1β secretion, as it was shown that HIFα, which is stabilized by cobalt ions [24], is involved in IL-1β biosynthesis [35] Interestingly, MCP-1, which was upregulated in debris-induced inflammation [7], was shown to be decreased in gene expression as well as protein biosynthesis after treatment with cobalt and nickel ions in THP-1 macrophages, and was not released from THP-1 monocytes at all despite increased gene expression. A similar effect was observed in THP-1 monocytes for IL-8, which showed a significant elevation in gene expression level, while the protein release was significantly decreased compared to untreated controls.…”

Dexmedetomidine protects against high mobility group box 1‐induced cellular injury by inhibiting pyroptosis

“…As expected, DEX pretreatment effectively improved the survival rate of BMDMs and reduces the production of pro‐inflammatory cytokines, such as TNF‐α, IL‐1β, IL‐18 after the addition of HMGB1. The overproduction of these pro‐inflammatory cytokines is thought to require the activation of MAP kinases, including ERK1/2, JNK, and p38 (Zarubin and Han, ; Liu et al, ; Talwar et al, ). Consistently, we also found that DEX reduces the production of pro‐inflammatory cytokines via inhibition of ERK1/2 and P38 phosphorylation in BMDMs in response to HMGB1 treatment.…”