Back to Search
Start Over
Blocking Interleukin (IL)4- and IL13-Mediated Phosphorylation of STAT6 (Tyr641) Decreases M2 Polarization of Macrophages and Protects Against Macrophage-Mediated Radioresistance of Inflammatory Breast Cancer.
- Source :
-
International Journal of Radiation Oncology, Biology, Physics . Mar2018, Vol. 100 Issue 4, p1034-1043. 10p. - Publication Year :
- 2018
-
Abstract
- <bold>Purpose: </bold>To determine the role of macrophage polarization on the response of inflammatory breast cancer (IBC) cells to radiation and whether modulation of macrophage plasticity can alter radiation response.<bold>Methods and Materials: </bold>The human THP-1 monocyte cell line and primary human monocytes isolated from peripheral blood mononuclear cells were differentiated into macrophages and polarized to either an "antitumor" (M1) or a "protumor" (M2) phenotype. These polarized macrophages were co-cultured with IBC cells (SUM149, KPL4, MDA-IBC3, or SUM190) without direct contact for 24 hours, then subjected to irradiation (0, 2, 4, or 6 Gy). Interleukin (IL)4/IL13-induced activation of STAT6 signaling was measured by Western blotting of phospho-STAT6 (Tyr641), and expression of M2 polarization gene markers (CD206, fibronectin, and CCL22) was measured by quantitative polymerase chain reaction.<bold>Results: </bold>Expression of M2 polarization markers was higher in M2-polarized macrophages after IL4/IL13 treatment than in control (M0) or M1-polarized macrophages. Co-culture of IBC cell lines with M1-polarized THP-1 macrophages mediated radiosensitivity of IBC cells, whereas co-culture with M2-polarized macrophages mediated radioresistance. Phosphopeptide mimetic PM37, targeting the SH2 domain of STAT6, prevented and reversed IL4/IL13-mediated STAT6 phosphorylation (Tyr641) and decreased the expression of M2 polarization markers. Pretreatment of M2-THP1 macrophages with PM37 reduced the radioresistance they induced in IBC cells after co-culture. Targeted proteomics analysis of IBC KPL4 cells using a kinase antibody array revealed induction of protein kinase C zeta (PRKCZ) in these cells only after co-culture with M2-THP1 macrophages, which was prevented by PM37 pretreatment. KPL4 cells with stable short hairpin RNA knockdown of PRKCZ exhibited lower radioresistance after M2-THP1 co-culture.<bold>Conclusions: </bold>These data suggest that inhibition of M2 polarization of macrophages by PM37 can prevent radioresistance of IBC by down-regulating PRKCZ. [ABSTRACT FROM AUTHOR]
- Subjects :
- *INTERLEUKIN-4
*INTERLEUKIN-3
*PHOSPHORYLATION
*MACROPHAGES
*BREAST cancer
*PROTEIN metabolism
*BIOCHEMISTRY
*BREAST tumors
*CARRIER proteins
*CELL lines
*CELL physiology
*CELL receptors
*COMPARATIVE studies
*CYTOKINES
*FIBRONECTINS
*GENES
*INDUSTRIES
*INTERLEUKINS
*PHENOMENOLOGY
*RESEARCH methodology
*MEDICAL cooperation
*PEPTIDES
*PROTEINS
*RADIATION
*RESEARCH
*RESEARCH funding
*RNA
*TISSUE culture
*TRANSFERASES
*PHENOTYPES
*GENETIC markers
*EVALUATION research
*CHEMICAL inhibitors
*PHYSIOLOGY
Subjects
Details
- Language :
- English
- ISSN :
- 03603016
- Volume :
- 100
- Issue :
- 4
- Database :
- Academic Search Index
- Journal :
- International Journal of Radiation Oncology, Biology, Physics
- Publication Type :
- Academic Journal
- Accession number :
- 128002106
- Full Text :
- https://doi.org/10.1016/j.ijrobp.2017.11.043