Lung tumor growth is stimulated in IFN-gamma-/- mice and inhibited in IL-4Ralpha-/- mice

Abstract

Background: Alternative (M2) macrophage activation is associated with tumor development in many tumor types, including those in the lung. Herein the biological consequences of forcing classical (M1) or alternative (M2) macrophage activation on lung tumor development are examined.

Materials and methods: Urethane-induced lung tumor multiplicity and size were compared in IFN-gamma(-/-) mice which lack M1 macrophage activation, IL-4Ralpha(-/-) mice which lack M2 macrophage activation, and wild-type BALB/cJ (background strain of the IFN-gamma(-/-) and IL-4Ralpha(-/-) mice) mice. Tumor-associated macrophage (TAM) and bone marrow-derived monocyte (BDMC) activation were each examined.

Results: The TAMs and BDMCs in the IFN-gamma(-/-) mice exhibited M2 activation, and their lung tumors were significantly larger than those in the wild-type mice. In contrast, urethane-treated IL-4Ralpha(-/-) mice, whose TAMs and BDMCs were M1 activated, developed smaller tumors than the wild-type mice.

Conclusion: Altered innate immunity can diminish or accelerate lung tumor progression in response to defective cytokine signaling.

Figure 1

Influence of genetic ablation of IFN-γ and IL-4 on urethane-induced tumor development and BAL macrophage infiltration. Tumor diameter (A), tumor multiplicity (B), and BAL macrophage concentration (C) in IL-4Rα^-/- (Δ) and IFN-γ^-/- (○) mice compared to wild-type controls (■) as a function of time after urethane treatment. *p<0.05, **p<0.001 vs. wild-type; data represents the mean ± SEM.

Figure 2

TAM and BDMC activation during urethane-induced tumorigenesis in IFN-γ^-/- and IL-4Rα^-/- mice. Tumor-associated BAL macrophages (F4/80): green, BDMCs (BM. CD-68): green, arginase I: blue, iNOS: red, 32 weeks after the first urethane injection in (A) wild-type controls, (B) IFN-γ^-/- mice and (C) IL-4Rα^-/- mice. Co-localization of F4/80 and iNOS or arginase I indicates that the cells staining for iNOS and arginase I are indeed macrophages. Final magnification 630×.

Figure 3

The presence of TIMs in IL-4Rα^-/- and IFN-γ^-/- mice. (A) Macrophages (F4/80) stained dark brown in uninvolved lung tissue adjacent to tumors (TAMs, right column) and within the tumor parenchyma (TIMs, left column) at 32 weeks after urethane induction. Final magnification 400×. (B) TIMs at 32 weeks. **p<0.001 compared to wild-type and IFN-γ^-/- mice. Data represents the mean ± SEM. (C) iNOS immunohistochemical staining in TIMs (circled) 32 weeks after urethane treatment in IL-4Rα^-/- mice.