Role of leptin as an immunomodulator of blood mononuclear cells: mechanisms of action.
Leptin is a an adipocyte-secreted hormone that regulates weight centrally. However, the leptin receptor is expressed not only in the central nervous system, but also in peripheral tissues, such as haematopoietic and immune systems. Therefore, the physiological role of leptin should not be limited to the regulation of food intake and energy expenditure. Moreover, the leptin receptor bears homology to members of the class I cytokine family, and recent data have demonstrated that leptin is able to modulate the immune response. Thus, the leptin receptor is expressed in human peripheral blood mononuclear cells, mediating the leptin effect on proliferation and activation. In vitro activation and HIV infection in vivo induce the expression of the long isoform of the leptin receptor in mononuclear cells. Also, leptin stimulates the production of proinflammatory cytokines from cultured monocytes and enhances the production of Th1 type cytokines from stimulated lymphocytes. Moreover, leptin has a trophic effect on monocytes, preventing apoptosis induced by serum deprivation. Leptin stimulation activates JAK-STAT, IRS-1-PI3K and MAPK signalling pathways. Leptin also stimulates Tyr-phosphorylation of the RNA-binding protein Sam68 mediating the dissociation from RNA. In this way, leptin signalling could modulate RNA metabolism. These signal transduction pathways provide possible mechanisms whereby leptin may modulate activation of peripheral blood mononuclear cells. Therefore, these data support the hypothesis regarding leptin as a proinflammatory cytokine with a possible role as a link between the nutritional status and the immune response. Moreover, these immunoregulatory functions of leptin could have some relevance in the pathophysiology of obesity.
Sánchez-Margalet
V
V
Department of Clinical Biochemistry, Investigation Unit, University Hospital Virgen Macarena, Seville, Spain. margalet@us.es
Martín-Romero
C
C
Santos-Alvarez
J
J
Goberna
R
R
Najib
S
S
Gonzalez-Yanes
C
C
D017667:Adipocytes / Q000378:metabolism*; D017209:Apoptosis; D001327:Autoimmune Diseases / Q000276:immunology; D002478:Cells, Cultured; D016207:Cytokines / Q000276:immunology; D006801:Humans; D053613:Janus Kinase 1; D020738:Leptin / Q000276:immunology* / Q000494:pharmacology; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000276:immunology*; D008213:Lymphocyte Activation; D020935:MAP Kinase Signaling System; D009752:Nutritional Status; D009765:Obesity / Q000276:immunology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D020033:Protein Isoforms / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism*; D054411:Receptors, Leptin; D015398:Signal Transduction / Q000502:physiology*; D018417:Th1 Cells / Q000378:metabolism
D016207:Cytokines; D053613:Janus Kinase 1; D020738:Leptin; D019869:Phosphatidylinositol 3-Kinases; D020033:Protein Isoforms; D011505:Protein-Tyrosine Kinases; D011956:Receptors, Cell Surface; D054411:Receptors, Leptin; C515448:LEPR protein, human; C507904:JAK1 protein, human