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

Feb 28, 2017Cellular signalling

MKP-1 reduces inflammation by limiting IL-1β production through p38 activation and HIF-1α expression

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Circadian Biology on OpenScience ↗PubMed ↗DOI ↗

Abstract

MKP-1 deficiency in bone marrow derived macrophages resulted in increased IL-1β production following LPS challenge.

MKP-1 regulates the expression of HIF-1α in response to LPS.
Deficient MKP-1 macrophages showed higher levels of reactive oxygen species (ROS) and HIF-1α expression.
Expression levels of prolyl hydroxylases, which help destabilize HIF-1α, were significantly decreased in MKP-1 deficient macrophages.
Inhibition of HIF-1α reduced IL-1β production triggered by LPS at both transcript and protein levels.
Inhibiting p38 MAP kinase led to decreased levels of pro-IL-1β, HIF-1α, and ROS in MKP-1 deficient macrophages.

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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.

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

Abstract

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