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Table 1.  

Adipokine Effects on Innate and Adaptive Immunity

Table 2.  

Adipokines in Rheumatic Diseases

Adipokines As Emerging Mediators of Immune Response and Inflammation

Authors: Francisca Lago, MD; Carlos Dieguez, MD; Juan Gómez-Reino, MD; Oreste Gualillo, MDFaculty and Disclosures

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Summary and Introduction

Summary

The scientific interest in the biology of white adipose tissue (WAT) has increased since the discovery of leptin in 1994. The description of the product of the gene obese (ob) demonstrated the role of adipose tissue in the physiopathology of obesity-related diseases, and helped to increase the identification of numerous other adipokines, many of a pro-inflammatory nature. It has become increasingly evident that WAT-derived adipokines can be considered as a hub between obesity-related exogenous factors, such as nutrition and lifestyle, and the molecular events that lead to metabolic syndrome, inflammatory and/or autoimmune conditions, and rheumatic diseases. In this Review, we will discuss the progress in adipokine research, focusing particular attention to the roles of leptin, adiponectin, resistin, visfatin, and other recently identified adipokines in inflammatory, autoimmune and rheumatic diseases.

Introduction

The Two Faces of White Adipose Tissue. The theory that white adipose tissue (WAT) could be an active contributor to whole-body homeostasis rather than just a fat depot became tangible with the discovery of leptin in 1994.[1] This 16 kDa protein was found to be the product of the gene obese (ob), which is mutated in the murine form of hereditary obesity. WAT has since been found to produce more than 50 cytokines and other molecules (Figure 1). These adipokinesengage, through endocrine, paracrine, autocrine or juxtacrine mechanisms of action, in a wide variety of physiological or pathological processes,including immunity and inflammation.[2]

Figure 1. (click image to zoom) The multiple functions of white adipose tissue include the synthesis and secretion of adipokines, and the uptake, storage and synthesis of lipids. White adipose tissue, the main energy store of the body, is also a source of proinflammatory factors that modulate the inflammatory response and promoteatherosclerosis, vascular dysfunction and insulin resistance. Inflammatory or immune diseases to which the major adipokines contribute by action or omission are depicted in boxes. Adipocyte-derived factors and their downstream signals might constitute therapeutic options for the treatment of these diseases. Abbreviations: CCL = CC-chemokine ligand (CCL); CXCL = CXC-chemokine ligand (CXCL); IL = interleukin; IL1-RA = interleukin-1-receptorantagonist; NGF = nerve growth factor; PAI1 = plasminogen activator inhibitor 1;TNF = tumor necrosis factor; VEGF = vascular endothelial growth factor.

It is important to underline that the term 'adipokine' is generally applied to biologically active substances found in the adipocytes of WAT; however, these factors might be synthesized at other sites and participate in functions unrelated to those within WAT.[3] Obesity, the condition initially spurring the flood of research on WAT, is now regarded as a pro-inflammatory state, and several markers of inflammation have been found to be elevated in obese subjects. Adipokines include a variety of pro-inflammatory peptides (including tumor necrosis factor[TNF], the secretion of which by adipocytes was observed even before the discovery of leptin).[4] These pro-inflammatory adipokines appear to contribute strikingly to the 'low-grade inflammatory state' of obese subjects, setting up a cluster of metabolic aberrations including cardiovascular complications and autoimmune inflammatory diseases. It is noteworthy that adipokine production by WAT in obesity is strongly influenced by the presence of infiltrating macrophages,through mutual crosstalk. Macrophages are an additional source of soluble mediators and might contribute and perpetuate local and systemic inflammation.[5] WAT also produces, presumablyas an adaptive response, anti-inflammatory factors such as interleukin (IL)-1-receptor antagonist(IL-1RA), which binds competitively to the IL-1 receptor without triggering activity within the cell, and IL-10 (circulating levels of which are also elevated in obese individuals). IL-1RA is markedly increased in human obese patients; data from rodents suggest that this endogenous antagonist has important central and peripheral functions including increased adipogenesis and acquired resistance to leptin. In addition, the ratio of IL-1RA to IL-1 is in favor of IL-1RA, and interferon (IFN)-β is likely to be the best inducer of IL-1RA in WAT. Curiously, IFN-β is unable to modulate either leptin or adiponectin in WAT.[6]

This Review will address the recent findings concerning the involvement of adipokines in inflammatory and immune responses, and will concentrate on the roles of the more recently discovered agents in articular degenerative diseases, such as rheumatoid arthritis (RA) and osteoarthritis.

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