Functional role of Akt in macrophage-mediated innate immunity

Yong Gyu Lee¹, Jaehwi Lee², Se Eun Byeon¹, Dae Sung Yoo¹, Min Ho Kim¹, Song Yi Lee¹, Jae Youl Cho¹

1College of Biomedical Science, and Institute of Bioscience and Biotechnology, Kangwon National University, Chuncheon 200-701, Korea, ² College of Pharmacy, Chung-Ang University, Seoul 156-756, Korea

TABLE OF CONTENTS

1. Abstract

2. Introduction

3. Structure and function of Akt

3.1. Akt

3.2. Akt deficiency

3.3. Akt substrate proteins

3.4. Expression and activity in macrophages

3.5. Akt-mediated activation signaling in macrophages

4. Akt in macrophage-mediated innate immunity

4.1. Inflammatory gene expression

4.2. Phagocytosis

4.3. Macrophage migration and chemotaxis

4.4. LPS tolerance

5. Development of Akt inhibitors as new immunosuppressive drugs

5.1. Akt inhibitor development

5.2. Akt inhibitors that inhibit production of inflammatory mediators

5.3. Akt inhibitors with in vivo therapeutic effects in inflammatory models

5.4. Novel Akt binding site: implications for development of a novel class of anti-inflammatory Akt inhibitors

6. Summary and perspective

7. References

1. ABSTRACT

Akt (protein kinase B) is a serine/threonine protein kinase that regulates cell metabolism, survival and proliferation. Recent studies of the role of Akt in phagocytosis, intracellular bacterial infections, LPS tolerance, production of inflammatory cytokines and mediators, and migration during macrophage-mediated innate immunity strongly suggest a pivotal role for this enzyme in the functional activation of macrophages. Considering that a variety of inflammatory diseases, such as rheumatoid arthritis, atherosclerosis, diabetes, obesity, cancer and osteoporosis, are regulated by macrophage-mediated innate immunity, efforts should be more carefully focused on understanding the function of Akt in macrophage-mediated innate immunity. Although few studies have addressed this question, this review discusses recent findings that support an important role for Akt in macrophage-mediated innate immunity and underlines the need for trials to develop pharmaceutically useful drugs that target Akt for treatment of macrophage-mediated inflammatory diseases. The findings we review here suggest that a novel and safe Akt inhibitor with strong immunosuppressive and anti-inflammatory properties will be applied to various chronic inflammatory diseases in the near future.