Skip to main content
construction release_alert
Scholars@Duke will be undergoing maintenance April 11-15. Some features may be unavailable during this time.
cancel
Journal cover image

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.

Publication ,  Journal Article
Rahal, OM; Wolfe, AR; Mandal, PK; Larson, R; Tin, S; Jimenez, C; Zhang, D; Horton, J; Reuben, JM; McMurray, JS; Woodward, WA
Published in: Int J Radiat Oncol Biol Phys
March 15, 2018

PURPOSE: 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. METHODS AND MATERIALS: 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. RESULTS: 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. CONCLUSIONS: These data suggest that inhibition of M2 polarization of macrophages by PM37 can prevent radioresistance of IBC by down-regulating PRKCZ.

Duke Scholars

Altmetric Attention Stats
Dimensions Citation Stats

Published In

Int J Radiat Oncol Biol Phys

DOI

EISSN

1879-355X

Publication Date

March 15, 2018

Volume

100

Issue

4

Start / End Page

1034 / 1043

Location

United States

Related Subject Headings

  • src Homology Domains
  • Tumor Microenvironment
  • THP-1 Cells
  • STAT6 Transcription Factor
  • Receptors, Cell Surface
  • Radiation Tolerance
  • RNA, Small Interfering
  • Protein Kinase C
  • Phosphorylation
  • Phosphopeptides
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Rahal, O. M., Wolfe, A. R., Mandal, P. K., Larson, R., Tin, S., Jimenez, C., … Woodward, W. A. (2018). 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. Int J Radiat Oncol Biol Phys, 100(4), 1034–1043. https://doi.org/10.1016/j.ijrobp.2017.11.043
Rahal, Omar M., Adam R. Wolfe, Pijus K. Mandal, Richard Larson, Sanda Tin, Cristina Jimenez, Dadong Zhang, et al. “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.Int J Radiat Oncol Biol Phys 100, no. 4 (March 15, 2018): 1034–43. https://doi.org/10.1016/j.ijrobp.2017.11.043.
Rahal, Omar M., et al. “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.Int J Radiat Oncol Biol Phys, vol. 100, no. 4, Mar. 2018, pp. 1034–43. Pubmed, doi:10.1016/j.ijrobp.2017.11.043.
Rahal OM, Wolfe AR, Mandal PK, Larson R, Tin S, Jimenez C, Zhang D, Horton J, Reuben JM, McMurray JS, Woodward WA. 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. Int J Radiat Oncol Biol Phys. 2018 Mar 15;100(4):1034–1043.
Journal cover image

Published In

Int J Radiat Oncol Biol Phys

DOI

EISSN

1879-355X

Publication Date

March 15, 2018

Volume

100

Issue

4

Start / End Page

1034 / 1043

Location

United States

Related Subject Headings

  • src Homology Domains
  • Tumor Microenvironment
  • THP-1 Cells
  • STAT6 Transcription Factor
  • Receptors, Cell Surface
  • Radiation Tolerance
  • RNA, Small Interfering
  • Protein Kinase C
  • Phosphorylation
  • Phosphopeptides