Elsevier

Molecular Immunology

Volume 44, Issue 14, July 2007, Pages 3453-3461
Molecular Immunology

Loss of the innate immunity negative regulator IRAK-M leads to enhanced host immune defense against tumor growth

https://doi.org/10.1016/j.molimm.2007.03.018Get rights and content

Abstract

IRAK-M is a negative regulator of innate immunity signaling processes. Although attenuation of innate immunity may help to prevent excessive inflammation, it may also lead to compromised immune surveillance of tumor cells and contribute to tumor formation and growth. Here, we demonstrate that IRAK-M−/− mice are resistant to tumor growth upon inoculation with transplantable tumor cells. Immune cells from IRAK-M−/− mice are responsible for the anti-tumor effect, since adoptive transfer of splenocytes from IRAK-M−/− mice to wild type mice can transfer the tumor-resistant phenotype. Upon tumor cell challenge, there are elevated populations of CD4+ and CD8+ T cells and a decreased population of CD4+ CD25+Foxp3+ regulatory T cells in IRAK-M−/− splenocytes. Furthermore, we observe that IRAK-M deficiency leads to elevated proliferation and activation of T cells and B cells. Enhanced NFκB activation directly caused by IRAK-M deficiency may explain elevated activation of T and B cells. In addition, macrophages from IRAK-M−/− mice exhibit enhanced phagocytic function toward acetylated LDL and apoptotic thymocytes. Collectively, we demonstrate that IRAK-M is directly involved in the regulation of both innate and adaptive immune signaling processes, and deletion of IRAK-M enhances host anti-tumor immune response.

Introduction

Increasing evidence suggests that tumor formation and growth benefit in part from suppression and/or alteration of host immune system (de Visser et al., 2006). The mammalian immune system is composed of two major arms: innate and adaptive immunity. Innate immunity is the first line of defense and senses abnormalities both outside and inside of host cells. Signals processed and released from innate immune cells can subsequently regulate T cell- and B cell-mediated adaptive immune responses. Compromising either innate or adaptive immunity may subject the host to chronic diseases such as tumor formation and progression. Indeed, extensive human clinical and animal tumor model studies indicate that tumor tissues as well as circulating immune cells within tumor-bearing hosts tend to have decreased CD8+ cytotoxic T lymphocytes, increased population of regulatory CD4+CD25+Foxp3+ T cells, and altered activities of macrophages and dendritic cells (Curiel et al., 2004, Ichihara et al., 2003, Klein et al., 2003, Mantovani et al., 2002, Vicari et al., 2002).

Toll-like receptor (TLR)-mediated signaling processes are critical for both innate and adaptive immune responses (Pasare and Medzhitov, 2005). Activation of TLR signaling pathways can lead to the production of cytokines and co-stimulatory molecules, which may further activate natural killer and tumor-reactive T cells, and enhance host anti-tumor response. Strategies using extra-cellular TLR agonists to boost innate immunity have been tested and shown in several cases to attenuate tumor growth (Akazawa et al., 2004, Zaks et al., 2006). However, the role of the TLR intra-cellular signaling network in tumor immune surveillance is poorly defined. Among the downstream signaling molecules, there is a family of interleukin-1 receptor-associated kinases (IRAKs). IRAK-4, 2, and 1 are involved in positively regulating innate and adaptive immunity by facilitating the expression of various inflammatory mediators, and enhancing proliferation and activation of various immune cells (Day et al., 2004, Ohnuma et al., 2005, Rosati and Martin, 2002, Suzuki et al., 2003). In contrast, IRAK-M is a negative regulator counteracting these effects (Kobayashi et al., 2002, Nakayama et al., 2004). It is likely that IRAK-M may serve as a double-edged sword. The presence of IRAK-M helps to de-activate innate immunity signaling and prevent excessive inflammatory responses. On the other hand, cancer cells may exploit the inhibitory function of IRAK-M to evade host immune surveillance. Indeed, it has been reported that IRAK-M levels are elevated in tumor tissues and may compromise the human host immune defense and facilitate tumor progression (del Fresno et al., 2005, Deng et al., 2006).

In this study, we have therefore tested the hypothesis that IRAK-M deficient mice may have enhanced anti-tumor response. We compared the tumor growth in wild type and IRAK-M−/− mice following injection with transplantable murine tumor cells such as B16-F0 or TM-7. Furthermore, we analyzed the immune cell populations using flow cytometry in tumor cell-injected wild type and IRAK-M−/− mice. The contribution of IRAK-M to T cell proliferation and cytotoxicity, B cell expression of co-stimulatory molecules, and macrophage activation were subsequently examined. We conclude that IRAK-M deficiency leads to enhanced functions of immune cells including macrophages, T and B cells, which may collectively contribute to host resistance to tumor growth.

Section snippets

Mice and in vivo tumor model

IRAK-1−/− mice of C57BL6 background were a kind gift from Dr. James Thomas from the University of Texas Southwestern Medical School (Thomas et al., 1999). IRAK-M−/− mice of C57BL/6 background were obtained from Dr. Richard Flavell at Yale University (Kobayashi et al., 2002). IRAK-1−/− mice were screened by PCR using the forward primer 5′-gccttctatcgccttcttgacg-3′ and reverse primer 5′-gcctctgtaagagatcaggtag-3′. IRAK-M mice were screened by PCR using the forward primer

IRAK-M deficient mice are resistant to tumor growth following inoculation with transplantable tumor cells

To determine whether IRAK-M deficiency renders enhanced anti-tumor response, we examined tumor formation and growth in wild type C57BL6 and IRAK-M−/− mice following injection of transplantable murine B16-F0 or TM-7 tumor cells. Subcutaneous injection of either B16-F0 or TM-7 tumor cells to wild type C57BL6 mice can lead to tumor formation. Both IRAK-M−/− and IRAK-1−/− mice are of C15BL6 background. First, we injected 5 × 104 B16 cells/per mouse s.c. into the lower back of the C57/BL6 wild type,

Discussion

In this study, we have demonstrated that IRAK-M deficiency leads to enhanced host protection against tumor growth. Elevated immune cell functions, including increased T cell proliferation and activation, decreased regulatory T cell population, increased expression of co-stimulatory markers on B cells, and enhanced phagocytosis of macrophages, may collectively contribute to anti-tumor immunity observed in IRAK-M−/− mice.

It is likely that IRAK-M deficiency may lead to increased expression of

Disclosures

The authors have no financial conflict of interest.

Acknowledgements

We are grateful to the technical help of Andrew Becker in our laboratory. This work was supported by grants from US NIH to L.L.

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