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MAP3K8 kinase regulates myeloma growth by cell-autonomous and non-autonomous mechanisms involving myeloma-associated monocytes/macrophages.

ABSTRACT: Benefit from cytotoxic therapy in myeloma may be limited by the persistence of residual tumour cells within protective niches. We have previously shown that monocytes/macrophages acquire a proinflammatory transcriptional profile in the myeloma microenvironment. Here we report constitutive activation of MAP3K8 kinase-dependent pathways that regulate the magnitude and extent of inflammatory activity of monocytes/macrophages within myeloma niches. In myeloma tumour cells, MAP3K8 acts as mitogen-induced MAP3K in mitosis and is required for TNF?-mediated ERK activation. Pharmacological MAP3K8 inhibition results in dose-dependent, tumour cell-autonomous apoptosis despite contact with primary stroma. MAP3K8 blockade may disrupt crucial macrophage-tumour cell interactions within myeloma niches.

SUBMITTER: Hebron E

PROVIDER: S-EPMC3594344 | biostudies-literature | 2013 Mar

REPOSITORIES: biostudies-literature

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MAP3K8 kinase regulates myeloma growth by cell-autonomous and non-autonomous mechanisms involving myeloma-associated monocytes/macrophages.

Hebron Ellen E Hope Chelsea C Kim Jaehyup J Jensen Jeffrey L JL Jensen Jeffrey L JL Flanagan Claire C Bhatia Neehar N Maroulakou Ioanna I Mitsiades Constantine C Miyamoto Shigeki S Callander Natalie N Hematti Peiman P Asimakopoulos Fotis F

British journal of haematology 20121218 6

Benefit from cytotoxic therapy in myeloma may be limited by the persistence of residual tumour cells within protective niches. We have previously shown that monocytes/macrophages acquire a proinflammatory transcriptional profile in the myeloma microenvironment. Here we report constitutive activation of MAP3K8 kinase-dependent pathways that regulate the magnitude and extent of inflammatory activity of monocytes/macrophages within myeloma niches. In myeloma tumour cells, MAP3K8 acts as mitogen-ind ...[more]

PMID: 23252623

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Project description:IntroductionInflammatory arthritis is a progressive disease with chronic inflammation of joints, which is mainly characterized by the infiltration of immune cells and synovial hyperproliferation. Monocytes migrate towards inflamed areas and differentiate into macrophages. In inflamed tissues, much lower oxygen levels (hypoxia) are present in comparison to the peripheral blood. Hence, a metabolic adaptation process must take place. Other studies suggest that Hypoxia Inducible Factor 1-alpha (HIF-1?) may regulate this process, but the mechanism involved for human monocytes is not yet clear. To address this issue, we analyzed the expression and function of HIF-1? in monocytes and macrophages, but also considered alternative pathways involving nuclear factor of kappa light polypeptide gene enhancer in B-cells (NF?B).MethodsIsolated human CD14? monocytes were incubated under normoxia and hypoxia conditions with or without phorbol 12-myristate 13-acetate (PMA) stimulation, respectively. Nuclear and cytosolic fractions were prepared in order to detect HIF-1? and NF?B by immunoblot. For the experiments with macrophages, primary human monocytes were differentiated into human monocyte derived macrophages (hMDM) using human macrophage colony-stimulating factor (hM-CSF). The effects of normoxia and hypoxia on gene expression were compared between monocytes and hMDMs using quantitative PCR (quantitative polymerase chain reaction).ResultsWe demonstrate, using primary human monocytes and hMDM, that the localization of transcription factor HIF-1? during the differentiation process is shifted from the cytosol (in monocytes) into the nucleus (in macrophages), apparently as an adaptation to a low oxygen environment. For this localization change, protein kinase C alpha/beta 1 (PKC-?/??) plays an important role. In monocytes, it is NF?B1, and not HIF-1?, which is of central importance for the expression of hypoxia-adjusted genes.ConclusionsThese data demonstrate that during differentiation of monocytes into macrophages, crucial cellular adaptation mechanisms are decisively changed.

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MAP3K8 kinase regulates myeloma growth by cell-autonomous and non-autonomous mechanisms involving myeloma-associated monocytes/macrophages.

Publications

MAP3K8 kinase regulates myeloma growth by cell-autonomous and non-autonomous mechanisms involving myeloma-associated monocytes/macrophages.

Similar Datasets

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