Gut-derived Endotoxin-TLR4 Signaling Drives MYC-Ig Translocation to Promote Lymphoproliferation through c-JUN and STAT3 Activation.

Synergism between obesity and virus infection promotes the development of B-cell lymphoma. In this study, we tested whether obesity-associated endotoxin release induced activation-induced cytidine deaminase (AID). TLR4 activation in turn caused c-JUN-dependent and STAT3-dependent translocations of MYC loci to suppress transactivation of CD95/FAS. We used viral nucleocapside Core transgenic (Tg) mice fed alcohol Western diet to determine whether oncogenesis arising from obesity and chronic virus infection occurred through TLR4-c-JUN-STAT3 pathways. Our results showed B cell-specific, c-Jun and/or Stat3 disruption reduced the incidence of splenomegaly in these mice. AID-dependent t(8;14) translocation was observed between the Ig promoter and MYC loci. Comparison with human B cells showed MYC-immunoglobulin (Ig) translocations after virus infection with lipopolysaccharide stimulation. Accordingly, human patients with lymphoma with virus infections and obesity showed a 40% incidence of MYC-Ig translocations. Thus, obesity and virus infection promote AID-mediated translocation between the Ig promoter and MYC through the TLR4-c-JUN axis, resulting in lymphoproliferation. Taken together, preventative treatment targeting either c-JUN and/or STAT3 may be effective strategies to prevent tumor development. IMPLICATIONS: Obesity increases gut-derived endotoxin which induces Toll-like receptor-mediated MYC-Ig translocation via c-JUN-STAT3, leading to lymphoproliferation.

[Significance of plasmic homocysteine, folate and Vitamin B(12) in ulcerative colitis].

OBJECTIVE: To investigate the clinical significance of plasmic homocysteine (Hcy), folate (FA) and Vitamin B(12) (VitB(12)) in patients with ulcerative colitis (UC). METHODS: Plasmic Hcy in 112 cases of UC patients and 110 controls were detected by HPLC-FD method. Plasmic FA, VitB(12) in 76 cases of UC patients and 12 controls were detected by enzyme-linked immunosorbent assay (ELISA) method. RESULTS: The level of plasmic Hcy in UC patients was(11.27±7.26) µmol/L, significantly higher than that in controls[(8.19±4.81) µmol/L, P<0.05], and was not significantly correlated with disease index, extent and duration of UC(P>0.05). The level of FA and VitB(12) in UC patients were (7.64±1.95) nmol/L and (108.64±32.22) pmol/L respectively, lower than those in controls[(9.14±1.23) nmol/L and (112.64±33.33) pmol/L, P<0.05]. The level of plasmic Hcy was negatively correlated with the level of FA and VitB(12) in UC patients(P<0.05). The level of plasmic FA decreased to some extent with UC disease duration. CONCLUSION: Plasmic Hcy is elevated in UC patients, which may be related to the decrease of FA and VitB(12).