J Bacteriol Virol.  2013 Mar;43(1):1-8. 10.4167/jbv.2013.43.1.1.

Leptin: A Multifunctional Role as an Immunomodulator in Mycobacterial Lung Disease

Affiliations
  • 1Department of Microbiology and Institute of Immunology and Immunological Diseases, Yon-sei University College of Medicine, Seoul, Korea. jskim7488@yuhs.ac

Abstract

Leptin is a 16 kDa protein which consists of 167 amino acids. Leptin is considered as one of the adipokines, secreted by white adipocytes, and is the product of the obese (ob) gene. Recently, leptin is recognized as the immuno-stimulator which belongs to the same class of long chain helical cytokines such as interleukin (IL)-6. Leptin is related to the immune responses evoked by Mycobacterium tuberculosis infection. Thus, studies of association between immunomolecules including leptin and tuberculosis may contribute to provide an essential solution regulating adverse immune responses in several mycobacterial diseases. Leptin has a multifunctional role in the secretion of acute-phase cytokines including IL-1beta and tumor-necrosis factor-alpha (TNF-alpha), and links to T helper 1 (Th1) immune response. Moreover, the binding of leptin to leptin receptor (LepR) is important in that this binding involves janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway. In addition, the activation of LepR mediates extra-cellular signal-regulated kinase (ERK) and phosphoinositide 3 kinase (PI3K) pathways. Furthermore, many studies suggest that leptin may play a critical role in respiratory diseases including chronic obstructive pulmonary disease (COPD) and asthma as well as tuberculosis. These findings indicate that leptin is one of the important regulators for immune responses in respiratory diseases. We herein discuss the multifunctional role of leptin in mycobacterial lung disease, especially focusing on the related pathway to immune responses.

Keyword

Leptin; Mycobacterium tuberculosis; Lung disease; Immune response; Signal pathway

MeSH Terms

Adipocytes, White
Adipokines
Amino Acids
Asthma
Cytokines
Interleukins
Leptin
Lung
Lung Diseases
Mycobacterium tuberculosis
Phosphotransferases
Pulmonary Disease, Chronic Obstructive
Receptors, Leptin
Signal Transduction
Transducers
Tuberculosis
Adipokines
Amino Acids
Cytokines
Interleukins
Leptin
Phosphotransferases
Receptors, Leptin

Figure

  • Figure 1. Leptin and Leptin receptor (LepR) pathway. JAK2 associates with the receptor via the box1 motif. The long isoform leptin (L) receptor (LepRb) contains four important tyrosine residues (Tyr974, Tyr985, Tyr1077 and Tyr1138). These phosphorylated tyrosine residues provide docking sites for signalling proteins with SH2 domains. Most importantly, Tyr1138 recruits the transcription factor STAT3, which is subsequently phosphorylated by JAK2, dimerizes and translocates to the nucleus. The ERK members of the MAPK family are components of the well-defined Ras/Raf/MAPK signalling cascade and have become activated by leptin. Stimulation of the PI3K pathway by leptin represents a key cascade to exert several different effects of the hormone at multiple sites. JAK, Janus kinase; PI3K, Phosphatidylinositol 3-kinase; AKT/PKB, protein kinase B; eNOS, endothelial nitric oxide synthase; STAT, Signal Transducer and Activator of Transcription; NO, nitric oxide; MAP, Mitogen-activated protein.

  • Figure 2. Effect of leptin on immune cell differentiation and immune responses. Leptin affects both innate and adaptive immunity. In innate immunity, leptin modulates the activity and function of neutrophils by increasing chemotaxis and the secretion of oxygen radicals through direct and indirect mechanisms. In mice, leptin seems to activate neutrophils directly. In humans, the action of leptin seems to be mediated by TNF-α secreted by monocytes. Leptin increases phagocytosis by monocytes/macrophages and enhances the secretion of pro-inflammatory mediators of the acute-phase response and the expression of adhesion molecules. On NK cells, leptin increases cytotoxic ability and the secretion of perforin and IL-2. In adaptive immunity, leptin affects the generation, maturation and survival of thymic T cells by reducing their rate of apoptosis. On naive T-cell responses, leptin increases proliferation and IL-2 secretion through the activation of MAPK and PI3K pathways. On memory T cells, leptin promotes the switch towards Th1-cell immune responses by increasing IFN-γ and TNF-α secretion, the production of IgG2a by B cells and delayed-type hypersensitivity (DTH) responses. This process is then sustained by an autocrine loop of leptin secretion by Th1 cells. Finally, leptin has anti-apoptotic effects on mature T cells and on haematopoietic precursors.


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