Survival of ovarian carcinoma is associated with the abundance of immunosuppressed CD163(high) CD206(high) tumor-associated macrophages (TAMs) and high levels of arachidonic acid (AA) in the tumor microenvironment. Here, we show that both associations are functionally linked. Transcriptional profiling revealed that high CD163 and CD206/MRC1 expression in TAMs is strongly associated with an inhibition of cytokine-triggered signaling, mirrored by an impaired transcriptional response to interferons and IL-6 in monocyte-derived macrophages by AA. This inhibition of pro-inflammatory signaling is caused by dysfunctions of the cognate receptors, indicated by the inhibition of JAK1, JAK2, STAT1, and STAT3 phosphorylation, and by the displacement of the interferon receptor IFNAR1, STAT1 and other immune-regulatory proteins from lipid rafts. AA exposure led to a dramatic accumulation of free AA in lipid rafts, which appears to be mechanistically crucial, as the inhibition of its incorporation into phospholipids did not affect the AA-mediated interference with STAT1 phosphorylation. Inhibition of interferon-triggered STAT1 phosphorylation by AA was reversed by water-soluble cholesterol, known to prevent the perturbation of lipid raft structure by AA. These findings suggest that the pharmacologic restoration of lipid raft functions in TAMs may contribute to the development new therapeutic approaches.
- Hammoud, M. K.
- Dietze, R.
- Pesek, J.
- Finkernagel, F.
- Unger, A.
- Bieringer, T.
- Nist, A.
- Stiewe, T.
- Bhagwat, A. M.
- Nockher, W. A.
- Reinartz, S.
- Müller-Brüsselbach, S.
- Graumann, J.
- Müller, R.
Keywords
- Arachidonic Acid/metabolism
- Humans
- Macrophages/metabolism
- Membrane Microdomains/metabolism
- *Neoplasms/metabolism
- STAT1 Transcription Factor/metabolism
- Signal Transduction
- *Tumor Microenvironment
- Stat
- arachidonic acid
- interferon
- lipid rafts
- macrophage
- ovarian cancer microenvironment