Deficiencies of GM-CSF and interferon gamma link inflammation and cancer - PubMed (original) (raw)

Thomas Enzler et al. J Exp Med. 2003.

Abstract

Chronic inflammation contributes to carcinogenesis, but the underlying mechanisms are poorly understood. We report that aged granulocyte-macrophage colony stimulating factor (GM-CSF)-deficient mice develop a systemic lupus erythematosis (SLE)-like disorder associated with the impaired phagocytosis of apoptotic cells. Concurrent deficiency of interferon (IFN)-gamma attenuates the SLE, but promotes the formation of diverse hematologic and solid neoplasms within a background of persistent infection and inflammation. Whereas activated B cells show a resistance to fas-induced apoptosis, antimicrobial therapy prevents lymphomagenesis and solid tumor development. These findings demonstrate that the interplay of infectious agents with cytokine-mediated regulation of immune homeostasis is a critical determinant of cancer susceptibility.

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Figures

Figure 1.

Figure 1.

Aged GM-CSF– and GM-CSF/IL-3–deficient mice develop a SLE-like disorder. (A) Membrano-proliferative glomerulonephritis with Ig deposition in a GM-CSF-deficient mouse, anti-κ antibody, original magnification ×400. (B) B220+ B cell aggregates in the renal pelvis of a GM-CSF–deficient mouse, original magnification ×400. (C) Anti-double stranded DNA antibodies. (D) Anti-C1q reactivity.

Figure 2.

Figure 2.

Impaired phagocytosis of apoptotic cells in GM-CSF– and GM-CSF/IL-3–deficient mice. Dexamethasone-induced apoptotic thymocytes from GM-CSF–deficient mice were injected into the peritoneal cavities of wild-type or GM-CSF/IL-3–deficient mice. Stained cytospins of harvested cells from: (A) wild-type mouse, original magnification ×400. (B) GM-CSF/IL-3–deficient mouse, original magnification ×400. Similar results were obtained in five experiments, and GM-CSF-deficient mice manifested comparable defects. (C and D) Apoptotic thymocytes were labeled with 5[6]-TAMRA before injection, and FACS® was used to analyze the harvested peritoneal cells. (C) Wild-type mouse. (D) GM-CSF/IL-3–deficient mouse. Similar results were found in six experiments.

Figure 3.

Figure 3.

Infection, inflammation, and cancer in GM-CSF/IFN-γ– and GM-CSF/IL-3/IFN-γ–deficient mice. (A) Survival curves for mice singly or multiply deficient in GM-CSF, IL-3, and IFN-γ. The numbers of animals per cohort were: GM-CSF/IL-3/IFN-γ– (n = 29), GM-CSF/IFN-γ– (n = 44), IFN-γ– (n = 14), GM-CSF– (n = 18), GM-CSF/IL-3– (n = 18). (B) Spectrum and incidence of spontaneous tumors. The number of mice harboring tumors at autopsy is shown. (C) Lethal bacterial pneumonia, H&E stain, original magnification ×400. (D) Granulomatous inflammation with multinucleated giant cells, H&E stain, original magnification ×400. (E) Plasmacytoid lymphoma, H&E stain, original magnification ×400. (F) High grade large cell lymphoma, H&E stain, original magnification ×400. (G) Choriocarcinoma, H&E stain, original magnification ×200. (H) Mucin positive biliary tract/liver carcinoma, mucicarmine stain, original magnification ×400.

Figure 4.

Figure 4.

B cell lymphomas. (A) Tumor-derived DNA from six different lymphomas was analyzed by southern using a Jκ probe. The germline band is 2.7 kb. (B) Single cell lymphoma suspensions were stimulated with anti-CD40 antibodies, and spectral karyotyping of metaphase spreads was performed. Shown are clonal 12:1, 4:13, 13:4, and 1:6 chromosomal translocations in one case. Chromosomal abnormalities were found in 3 of 6 tumors. (C) Impaired fas-mediated apoptosis. Enriched splenic B cells (90% pure) were stimulated for 48 h with anti-CD40 antibody (after activation, >90% B cells), and then 106 cell aliquots were incubated with 1 μg of anti-fas antibody, 100 μM etoposide, 1 μM staurosporine, or 2 μg/ml of actinomycin D for 12 h and cell viability determined. Data are pooled from six experiments; fas-treated wild-type versus fas-treated GM-CSF/IL-3/IFN-γ deficient, P < 0.0001. Similar results were obtained with LPS (50 μg) stimulated B cells. A comparable fas-resistance was also found with GM-CSF/IFN-γ–deficient B cells. (D) TNF-α and IFN-γ are required for fas-mediated B cell apoptosis. The data are pooled from four experiments.

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