title: Modulation of mammalian circadian rhythms by tumor necrosis factor-α.
abstract: Systemic low doses of the endotoxin lipopolysaccharide (LPS, 100 µg/kg) administered during the early night induce phase-delays of locomotor activity rhythms in mice. Our aim was to evaluate the role of tumor necrosis factor (Tnf)-alpha and its receptor 1/p55 (Tnfr1) in the modulation of LPS-induced circadian effects on the suprachiasmatic nucleus (SCN). We observed that Tnfr1-defective mice (Tnfr1 KO), although exhibiting similar circadian behavior and light response to that of control mice, did not show LPS-induced phase-delays of locomotor activity rhythms, nor LPS-induced cFos and Per2 expression in the SCN and Per1 expression in the paraventricular hypothalamic nucleus (PVN) as compared to wild-type (WT) mice. We also analyzed Tnfr1 expression in the SCN of WT mice, peaking during the early night, when LPS has a circadian effect. Peripheral inoculation of LPS induced an increase in cytokine/chemokine levels (Tnf, Il-6 and Ccl2) in the SCN and in the PVN. In conclusion, in this study, we show that LPS-induced circadian responses are mediated by Tnf. Our results also suggest that this cytokine stimulates the SCN after LPS peripheral inoculation; and the time-related effect of LPS (i.e. phase shifts elicited only at early night) might depend on the increased levels of Tnfr1 expression. We also confirmed that LPS modulates clock gene expression in the SCN and PVN in WT but not in Tnfr1 KO mice.
  
  
  CONCLUSIONS
  We demonstrate a fundamental role for Tnf and its receptor in circadian modulation by immune stimuli at the level of the SCN biological clock.
authors: Laboratorio de Cronobiología, Universidad Nacional de Quilmes , Buenos Aires , Argentina.
authors: Natalia
authors: N
authors: Paladino
authors: Malena L
authors: ML
authors: Mul Fedele
authors: José M
authors: JM
authors: Duhart
authors: Luciano
authors: L
authors: Marpegan
authors: Diego A
authors: DA
authors: Golombek
mesh_terms: D000818:Animals; D001683:Biological Clocks / Q000187:drug effects / Q000528:radiation effects; D018932:Chemokine CCL2 / Q000378:metabolism; D002940:Circadian Rhythm / Q000187:drug effects / Q000528:radiation effects; D004334:Drug Administration Schedule; D015850:Interleukin-6 / Q000378:metabolism; D008027:Light; D008070:Lipopolysaccharides / Q000008:administration & dosage; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects / Q000528:radiation effects; D010286:Paraventricular Hypothalamic Nucleus / Q000378:metabolism; D017440:Photoperiod; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000172:deficiency / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects / Q000528:radiation effects; D013493:Suprachiasmatic Nucleus / Q000187:drug effects / Q000378:metabolism* / Q000528:radiation effects; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
chemical_list: C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D015850:Interleukin-6; D008070:Lipopolysaccharides; D047888:Receptors, Tumor Necrosis Factor, Type I; C506236:Tnfrsf1a protein, mouse; D014409:Tumor Necrosis Factor-alpha; C577686:interleukin-6, mouse
keywords: Circadian rhythms; TNF receptor 1; lipopolysaccharide; suprachiasmatic nucleus; tumor necrosis factor-alpha