p50 nuclear factor-kappaB overexpression in tumor-associated macrophages inhibits M1 inflammatory responses and antitumor resistance

Alessandra Saccani; Tiziana Schioppa; Chiara Porta; Subhra K Biswas; Manuela Nebuloni; Luca Vago; Barbara Bottazzi; Mario P Colombo; Alberto Mantovani; Antonio Sica

doi:10.1158/0008-5472.CAN-06-1867

p50 nuclear factor-kappaB overexpression in tumor-associated macrophages inhibits M1 inflammatory responses and antitumor resistance

Cancer Res. 2006 Dec 1;66(23):11432-40. doi: 10.1158/0008-5472.CAN-06-1867.

Authors

Alessandra Saccani¹, Tiziana Schioppa, Chiara Porta, Subhra K Biswas, Manuela Nebuloni, Luca Vago, Barbara Bottazzi, Mario P Colombo, Alberto Mantovani, Antonio Sica

Affiliation

¹ Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy.

PMID: 17145890
DOI: 10.1158/0008-5472.CAN-06-1867

Abstract

Tumor-associated macrophages (TAM) are a major inflammatory infiltrate in tumors and a major component of the protumor function of inflammation. TAM in established tumors generally have an M2 phenotype with defective production of interleukin-12 (IL-12) and high IL-10. Here, we report that defective responsiveness of TAM from a murine fibrosarcoma and human ovarian carcinoma to M1 activation signals was associated with a massive nuclear localization of the p50 nuclear factor-kappaB (NF-kappaB) inhibitory homodimer. p50 overexpression inhibited IL-12 expression in normal macrophages. TAM isolated from p50(-/-) mice showed normal production of M1 cytokines, associated with reduced growth of transplanted tumors. Bone marrow chimeras showed that p50 inactivation in hematopoietic cells was sufficient to result in reduced tumor growth. Thus, p50 NF-kappaB overexpression accounts for the inability of TAM to mount an effective M1 antitumor response capable of inhibiting tumor growth.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Active Transport, Cell Nucleus / drug effects
Animals
Blotting, Western
Bone Marrow Transplantation / methods
Cell Nucleus / drug effects
Cell Nucleus / metabolism
Cells, Cultured
Cytokines / genetics
Cytokines / metabolism*
Flow Cytometry
Gene Expression / genetics
Humans
Immunohistochemistry
Inflammation / genetics
Inflammation / metabolism
Inflammation / pathology
Inflammation Mediators / immunology
Inflammation Mediators / metabolism
Interleukin-10 / genetics
Interleukin-10 / metabolism
Interleukin-12 / genetics
Interleukin-12 / metabolism
Interleukin-6 / genetics
Interleukin-6 / metabolism
Lipopolysaccharides / pharmacology
Macrophages / immunology
Macrophages / metabolism*
Macrophages / pathology
Mice
Mice, Knockout
NF-kappa B p50 Subunit / deficiency
NF-kappa B p50 Subunit / genetics
NF-kappa B p50 Subunit / metabolism*
Neoplasms / genetics
Neoplasms / metabolism
Neoplasms / pathology*
RNA, Messenger / genetics
RNA, Messenger / metabolism
Tumor Necrosis Factor-alpha / genetics
Tumor Necrosis Factor-alpha / metabolism

Substances

Cytokines
Inflammation Mediators
Interleukin-6
Lipopolysaccharides
NF-kappa B p50 Subunit
RNA, Messenger
Tumor Necrosis Factor-alpha
Interleukin-10
Interleukin-12