Abstract
BackgroundUnder inflammatory conditions or during tumor progression macrophages acquire distinct phenotypes, with factors of the microenvironment such as hypoxia and transforming growth factor β (TGFβ) shaping their functional plasticity. TGFβ is among the factors causing alternative macrophage activation, which contributes to tissue regeneration and thus, resolution of inflammation but may also provoke tumor progression. However, the signal crosstalk between TGFβ and hypoxia is ill defined.ResultsExposing human primary macrophages to TGFβ elicited a rapid SMAD2/SMAD3 phosphorylation. This early TGFβ-signaling remained unaffected by hypoxia. However, with prolonged exposure periods to TGFβ/hypoxia the expression of SMAD2 declined because of decreased protein stability. In parallel, hypoxia increased mRNA and protein amount of the calpain regulatory subunit, with the further notion that TGFβ/hypoxia elicited calpain activation. The dual specific proteasome/calpain inhibitor MG132 and the specific calpain inhibitor 1 rescued SMAD2 degradation, substantiating the ability of calpain to degrade SMAD2. Decreased SMAD2 expression reduced TGFβ transcriptional activity of its target genes thrombospondin 1, dystonin, and matrix metalloproteinase 2.ConclusionsHypoxia interferes with TGFβ signaling in macrophages by calpain-mediated proteolysis of the central signaling component SMAD2.Electronic supplementary materialThe online version of this article (doi:10.1186/s13578-015-0026-x) contains supplementary material, which is available to authorized users.
Highlights
Macrophages are found throughout the body, where they contribute to tissue homeostasis and orchestrate innate as well as adaptive immune responses
An alternatively activated macrophage phenotype is elicited by interleukin-4 (IL-4), IL-10, or transforming growth factor ß (TGFß), which are produced by helper 2 or regulatory T cells, tumor cells, or macrophages themselves
Hypoxia attenuates TGFß-induced SMAD2 activation in macrophages Macrophages in the tumor microenvironment are exposed to hypoxia and TGFß but their signaling crosstalk has not been explored in detail
Summary
Macrophages are found throughout the body, where they contribute to tissue homeostasis and orchestrate innate as well as adaptive immune responses They display a remarkable plasticity, which allows them to change their functional repertoire with regard to the environment they are facing. An alternatively activated macrophage phenotype is elicited by interleukin-4 (IL-4), IL-10, or transforming growth factor ß (TGFß), which are produced by helper 2 or regulatory T cells, tumor cells, or macrophages themselves. Under inflammatory conditions or during tumor progression macrophages acquire distinct phenotypes, with factors of the microenvironment such as hypoxia and transforming growth factor β (TGFβ) shaping their functional plasticity. TGFβ is among the factors causing alternative macrophage activation, which contributes to tissue regeneration and resolution of inflammation but may provoke tumor progression. The signal crosstalk between TGFβ and hypoxia is ill defined
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