MK2 regulates macrophage chemokine activity and recruitment to promote colon tumor growth

Brandon B. Phinney, Anita L. Ray, Amanda S. Peretti, Stephanie J. Jerman, Carl Grim, Iryna Pinchuk, Ellen J. Beswick

Research output: Contribution to journalArticle

Abstract

A major risk factor for colon cancer growth and progression is chronic inflammation. We have shown that the MAPK-activated protein kinase 2 (MK2) pathway is critical for colon tumor growth in colitis-associated and spontaneous colon cancer models. This pathway is known to regulate expression of the tumor-promoting cytokines, IL-1, IL-6, and TNF-a. However, little is known about the ability of MK2 to regulate chemokine production. This is the first study to demonstrate this pathway also regulates the chemokines, MCP-1, Mip-1a, and Mip-2a (MMM). We show that these chemokines induce tumor cell growth and invasion in vitro and that MK2 inhibition suppresses tumor cell production of chemokines and reverses the resulting pro-tumorigenic effects. Addition of MMM to colon tumors in vivo significantly enhances tumor growth in control tumors and restores tumor growth in the presence of MK2 inhibition. We also demonstrate that MK2 signaling is critical for chemokine expression and macrophage influx to the colon tumor microenvironment. MK2 signaling in macrophages was essential for inflammatory cytokine/chemokine production, whereas MK2-/- macrophages or MK2 inhibition suppressed cytokine expression. We show that addition of bone marrow-derived macrophages to the tumor microenvironment enhances tumor growth in control tumors and restores tumor growth in tumors treated with MK2 inhibitors, while addition of MK2-/- macrophages had no effect. This is the first study to demonstrate the critical role of the MK2 pathway in chemokine production, macrophage influx, macrophage function, and tumor growth.

Original languageEnglish (US)
Article number1857
JournalFrontiers in Immunology
Volume9
Issue numberSEP
DOIs
StatePublished - Sep 21 2018

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Personnel Selection
Chemokines
Protein Kinases
Colon
Macrophages
Growth
Neoplasms
Tumor Microenvironment
Cytokines
Colonic Neoplasms
Critical Pathways
Colitis
Protein Kinase Inhibitors
Interleukin-1

Keywords

  • Chemokines
  • Colon tumor
  • Inflammation
  • Macrophages
  • MK2

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Phinney, B. B., Ray, A. L., Peretti, A. S., Jerman, S. J., Grim, C., Pinchuk, I., & Beswick, E. J. (2018). MK2 regulates macrophage chemokine activity and recruitment to promote colon tumor growth. Frontiers in Immunology, 9(SEP), [1857]. https://doi.org/10.3389/fimmu.2018.01857

MK2 regulates macrophage chemokine activity and recruitment to promote colon tumor growth. / Phinney, Brandon B.; Ray, Anita L.; Peretti, Amanda S.; Jerman, Stephanie J.; Grim, Carl; Pinchuk, Iryna; Beswick, Ellen J.

In: Frontiers in Immunology, Vol. 9, No. SEP, 1857, 21.09.2018.

Research output: Contribution to journalArticle

Phinney, BB, Ray, AL, Peretti, AS, Jerman, SJ, Grim, C, Pinchuk, I & Beswick, EJ 2018, 'MK2 regulates macrophage chemokine activity and recruitment to promote colon tumor growth', Frontiers in Immunology, vol. 9, no. SEP, 1857. https://doi.org/10.3389/fimmu.2018.01857
Phinney, Brandon B. ; Ray, Anita L. ; Peretti, Amanda S. ; Jerman, Stephanie J. ; Grim, Carl ; Pinchuk, Iryna ; Beswick, Ellen J. / MK2 regulates macrophage chemokine activity and recruitment to promote colon tumor growth. In: Frontiers in Immunology. 2018 ; Vol. 9, No. SEP.
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