Leptin inhibits apoptosis in thymus through a janus kinase-2-independent, insulin receptor substrate-1/phosphatidylinositol-3 kinase-dependent pathway.
The cytokine-like hormone leptin is known to exert important functions on the modulation of immune responses. Some of these effects are dependent on the property of leptin to modulate the apoptosis of thymic cells. In the present study, we used Wistar rats to investigate the molecular mechanisms involved in leptin-dependent control of apoptosis in thymus. Apoptosis was evaluated by flow cytometry and ELISA for nucleosome determination, whereas signal transduction was evaluated by immunoprecipitation, immunoblot, and confocal microscopy. The Ob receptor (ObR) was expressed in most thymic cells and its relative amount reduced progressively during thymocyte maturation. ObR expression was colocalized with Janus kinase (JAK)-2 and signal transducer and activator of transcription-3, and an acute, in vivo, injection of leptin promoted the tyrosine phosphorylation of JAK-2 and the engagement of signal transducer and activator of transcription-3. The treatment with leptin also led to the tyrosine phosphorylation of insulin receptor substrate (IRS)-1 and serine phosphorylation of Akt. Chronic treatment with leptin reduced thymic apoptosis, an effect that was not inhibited by the JAK inhibitor AG(490) but was significantly inhibited by the phosphatidylinositol 3-kinase inhibitor LY(294002) and an antisense oligonucleotide to IRS-1. Thus, leptin inhibits the apoptosis of thymic cells through a mechanism that is independent of the activation of JAK-2 but depends on the engagement of the IRS-1/phosphatidylinositol 3-kinase pathway.
Mansour
Eli
E
Departamento de Clínica Médica, Faculdade de Ciências Médicas-State University of Campinas, 13083-970 Campinas SP, Brazil.
Pereira
Fernanda G
FG
Araújo
Eliana P
EP
Amaral
Maria E C
ME
Morari
Joseane
J
Ferraroni
Natasha R
NR
Ferreira
Diogenes S
DS
Lorand-Metze
Irene
I
Velloso
Lício A
LA
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D055504:Insulin Receptor Substrate Proteins; D053614:Janus Kinase 2 / Q000502:physiology*; D020738:Leptin / Q000097:blood / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D010750:Phosphoproteins / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D011956:Receptors, Cell Surface / Q000032:analysis; D054411:Receptors, Leptin; D050796:STAT3 Transcription Factor / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects; D013950:Thymus Gland / Q000166:cytology / Q000187:drug effects*
D055504:Insulin Receptor Substrate Proteins; C526295:Irs1 protein, mouse; C526296:Irs1 protein, rat; D020738:Leptin; D010750:Phosphoproteins; D011956:Receptors, Cell Surface; D054411:Receptors, Leptin; D050796:STAT3 Transcription Factor; C515447:leptin receptor, mouse; D019869:Phosphatidylinositol 3-Kinases; C507927:Jak2 protein, rat; D053614:Janus Kinase 2; D051057:Proto-Oncogene Proteins c-akt