A distinct and unique transcriptional program expressed by tumor-associated macrophages (defective NF-κB and enhanced IRF-3/STAT1 activation)

Subhra K. Biswas, Lisa Gangi, Saki Paul, Tiziana Schioppa, Alessandra Saccani, Marina Sironi, Barbara Bottazzi, Andrea Doni, Bronte Vincenzo, Fabio Pasqualini, Luca Vago, Manuela Nebuloni, Alberto Mantovani, Antonio Sica

Research output: Contribution to journalArticle

Abstract

To identify the molecular basis underlying the functions of tumor-associated macrophages (TAMs), we characterized the gene expression profile of TAMs isolated from a murine fibrosarcoma in comparison with peritoneal macrophages (PECs) and myeloid suppressor cells (MSCs), using a cDNAmicroarray technology. Among the differentially expressed genes, 15 genes relevant to inflammation and immunity were validated by real-time polymerase chain reaction (PCR) and protein production. Resting TAMs showed a characteristic gene expression pattern with higher expression of genes coding for the immunosuppressive cytokine IL-10, phagocytosis-related receptors/molecules (Msr2 and C1q), and inflammatory chemokines (CCL2 and CCL5) as expected, as well as, unexpectedly, IFN-inducible chemokines (CXCL9, CXCL10, CXCL16). Immunohistology confirmed and extended the in vitro analysis by showing that TAMs express M2-associated molecules (eg, IL-10 and MGL1), as well as CCL2, CCL5, CXCL9, CXCL10, and CXCL16, but no appreciable NOS2. Lipopolysaccharide (LPS)-mediated activation of TAMs resulted in defective expression of several proinflammatory cytokines (eg, IL-1β, IL-6, TNF-α) and chemokines (eg, CCL3), as opposed to a strong up-regulation of immunosuppressive cytokines (IL-10, TGFβ) and IFN-inducible chemokines (CCL5, CXCL9, CXCL10, CXCL16). Thus, profiling of TAMs from a murine sarcoma revealed unexpected expression of IFN-inducible chemokines, associated with an M2 phenotype (IL-10high, IL-12low), and divergent regulation of the NF-κB versus the IRF-3/STAT1 pathway.

Original languageEnglish
Pages (from-to)2112-2122
Number of pages11
JournalBlood
Volume107
Issue number5
DOIs
Publication statusPublished - Mar 1 2006

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Macrophages
Tumors
Chemical activation
Chemokine CXCL9
Interleukin-10
Chemokine CCL5
Neoplasms
Immunosuppressive Agents
Cytokines
Genes
Chemokines
Gene expression
Chemokine CXCL10
Chemokine CCL3
Gene Expression
Chemokine CCL2
Fibrosarcoma
Peritoneal Macrophages
Myeloid Cells
Molecules

ASJC Scopus subject areas

  • Hematology

Cite this

A distinct and unique transcriptional program expressed by tumor-associated macrophages (defective NF-κB and enhanced IRF-3/STAT1 activation). / Biswas, Subhra K.; Gangi, Lisa; Paul, Saki; Schioppa, Tiziana; Saccani, Alessandra; Sironi, Marina; Bottazzi, Barbara; Doni, Andrea; Vincenzo, Bronte; Pasqualini, Fabio; Vago, Luca; Nebuloni, Manuela; Mantovani, Alberto; Sica, Antonio.

In: Blood, Vol. 107, No. 5, 01.03.2006, p. 2112-2122.

Research output: Contribution to journalArticle

Biswas, Subhra K. ; Gangi, Lisa ; Paul, Saki ; Schioppa, Tiziana ; Saccani, Alessandra ; Sironi, Marina ; Bottazzi, Barbara ; Doni, Andrea ; Vincenzo, Bronte ; Pasqualini, Fabio ; Vago, Luca ; Nebuloni, Manuela ; Mantovani, Alberto ; Sica, Antonio. / A distinct and unique transcriptional program expressed by tumor-associated macrophages (defective NF-κB and enhanced IRF-3/STAT1 activation). In: Blood. 2006 ; Vol. 107, No. 5. pp. 2112-2122.
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T1 - A distinct and unique transcriptional program expressed by tumor-associated macrophages (defective NF-κB and enhanced IRF-3/STAT1 activation)

AU - Biswas, Subhra K.

AU - Gangi, Lisa

AU - Paul, Saki

AU - Schioppa, Tiziana

AU - Saccani, Alessandra

AU - Sironi, Marina

AU - Bottazzi, Barbara

AU - Doni, Andrea

AU - Vincenzo, Bronte

AU - Pasqualini, Fabio

AU - Vago, Luca

AU - Nebuloni, Manuela

AU - Mantovani, Alberto

AU - Sica, Antonio

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N2 - To identify the molecular basis underlying the functions of tumor-associated macrophages (TAMs), we characterized the gene expression profile of TAMs isolated from a murine fibrosarcoma in comparison with peritoneal macrophages (PECs) and myeloid suppressor cells (MSCs), using a cDNAmicroarray technology. Among the differentially expressed genes, 15 genes relevant to inflammation and immunity were validated by real-time polymerase chain reaction (PCR) and protein production. Resting TAMs showed a characteristic gene expression pattern with higher expression of genes coding for the immunosuppressive cytokine IL-10, phagocytosis-related receptors/molecules (Msr2 and C1q), and inflammatory chemokines (CCL2 and CCL5) as expected, as well as, unexpectedly, IFN-inducible chemokines (CXCL9, CXCL10, CXCL16). Immunohistology confirmed and extended the in vitro analysis by showing that TAMs express M2-associated molecules (eg, IL-10 and MGL1), as well as CCL2, CCL5, CXCL9, CXCL10, and CXCL16, but no appreciable NOS2. Lipopolysaccharide (LPS)-mediated activation of TAMs resulted in defective expression of several proinflammatory cytokines (eg, IL-1β, IL-6, TNF-α) and chemokines (eg, CCL3), as opposed to a strong up-regulation of immunosuppressive cytokines (IL-10, TGFβ) and IFN-inducible chemokines (CCL5, CXCL9, CXCL10, CXCL16). Thus, profiling of TAMs from a murine sarcoma revealed unexpected expression of IFN-inducible chemokines, associated with an M2 phenotype (IL-10high, IL-12low), and divergent regulation of the NF-κB versus the IRF-3/STAT1 pathway.

AB - To identify the molecular basis underlying the functions of tumor-associated macrophages (TAMs), we characterized the gene expression profile of TAMs isolated from a murine fibrosarcoma in comparison with peritoneal macrophages (PECs) and myeloid suppressor cells (MSCs), using a cDNAmicroarray technology. Among the differentially expressed genes, 15 genes relevant to inflammation and immunity were validated by real-time polymerase chain reaction (PCR) and protein production. Resting TAMs showed a characteristic gene expression pattern with higher expression of genes coding for the immunosuppressive cytokine IL-10, phagocytosis-related receptors/molecules (Msr2 and C1q), and inflammatory chemokines (CCL2 and CCL5) as expected, as well as, unexpectedly, IFN-inducible chemokines (CXCL9, CXCL10, CXCL16). Immunohistology confirmed and extended the in vitro analysis by showing that TAMs express M2-associated molecules (eg, IL-10 and MGL1), as well as CCL2, CCL5, CXCL9, CXCL10, and CXCL16, but no appreciable NOS2. Lipopolysaccharide (LPS)-mediated activation of TAMs resulted in defective expression of several proinflammatory cytokines (eg, IL-1β, IL-6, TNF-α) and chemokines (eg, CCL3), as opposed to a strong up-regulation of immunosuppressive cytokines (IL-10, TGFβ) and IFN-inducible chemokines (CCL5, CXCL9, CXCL10, CXCL16). Thus, profiling of TAMs from a murine sarcoma revealed unexpected expression of IFN-inducible chemokines, associated with an M2 phenotype (IL-10high, IL-12low), and divergent regulation of the NF-κB versus the IRF-3/STAT1 pathway.

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