Inflammation Perturbs the IL-7 Axis, Promoting Senescence and Exhaustion that Broadly Characterize Immune Failure in Treated HIV Infection.

BACKGROUND: HIV-infected patients who fail to normalize CD4 T cells despite suppressive antiretroviral therapy have impaired immune homeostasis: diminished naive T-cell numbers, elevated T-cell turnover, senescence, and inflammation. METHODS: Blood samples from immune failures (n = 60), immune successes (n = 20), and healthy controls (n = 20) were examined for plasma interleukin (IL)-7 levels, for cellular expression of the IL-7Rα chain (CD127), for the exhaustion and senescence markers programed death 1 (PD-1) and CD57, and for the survival factor Bcl2. Because both inflammatory and homeostatic cytokines can induce T-cell cycling, we also examined the effects of these mediators on exhaustion and senescence markers. RESULTS: Plasma levels of IL-7 were elevated and both CD4 and CD8 T-cell CD127 expression was decreased in immune failure. Plasma levels of IL-7 correlated directly with naive CD4 T-cell counts in immune success and inversely with T-cell cycling (Ki67) in healthy controls and immune success, but not in immune failure. CD4 T-cell density of PD-1 was increased and Bcl2+ CD4 T cells were decreased in immune failure but not in immune success, whereas the proportion of T cells expressing CD57 was increased in immune failure. PD-1 and CD57 were induced on CD4 but not CD8 T cells by stimulation in vitro with inflammatory IL-1ß or homeostatic (IL-7) cytokines. CONCLUSIONS: Perturbation of the IL-7/IL-7 receptor axis, increased T-cell turnover, and increased senescence may reflect dysregulated responses to both homeostatic and inflammatory cytokines in immune failure patients.

Induction of intervertebral disc cell apoptosis and degeneration by chronic unpredictable stress.

OBJECT: The purpose of this study was to evaluate the effects of chronic unpredictable stress on the intervertebral discs of rats. METHODS: The cellular events involved in injury- and stress-induced disc degeneration were investigated in male Wistar rats. Disc degeneration and apoptosis were evaluated using microscopic (light and electron) and molecular (immunoblotting and immunohistochemistry) methods. Corticosterone levels were used as markers of stress and measured by radioimmunoassay. RESULTS: The data gathered in this study showed that chronic unpredictable stress can significantly increase corticosterone levels. Furthermore, biochemical markers of apoptosis (that is, increases in the Bax/Bcl2 ratio and TUNEL reactivity [p < 0.05]) were observed in the stressed animals. Electron and light microscopy also showed disc degeneration and apoptotic cells in the experimental groups. CONCLUSIONS: Taken together, these data demonstrated that chronic stress is most likely to be a risk factor for creating intervertebral disc degeneration and that programmed cell death may be one of the mechanisms of stress-induced disc degeneration.

P2Y12 protects platelets from apoptosis via PI3k-dependent Bak/Bax inactivation.

BACKGROUND: Platelet ADP receptor P2Y(12) is well studied and recognized as a key player in platelet activation, hemostasis and thrombosis. However, the role of P2Y(12) in platelet apoptosis remains unknown. OBJECTIVES: To evaluate the role of the P2Y(12) receptor in platelet apoptosis. METHODS: We used flow cytometry and Western blotting to assess apoptotic events in platelets treated with ABT-737 or ABT-263, and stored at 37°C, combined with P2Y(12) receptor antagonists or P2Y(12) -deficient mice. RESULTS: P2Y(12) activation attenuated apoptosis induced by ABT-737 in human and mouse platelets in vitro, evidenced by reduced phosphatidylserine (PS) exposure, diminished depolarization of mitochondrial inner transmembrane potential (ΔΨm) and decreased caspase-3 activation. Through increasing the phosphorylation level of Akt and Bad, and changing the interaction between different Bcl-2 family proteins, P2Y(12) activation inactivated Bak/Bax. This antiapoptotic effect could be abolished by P2Y(12) antagonism or PI3K inhibition. We also observed the antiapoptotic effect of P2Y(12) activation in platelets stored at 37°C. P2Y(12) activation improved the impaired activation responses of apoptotic platelets stressed by ABT-737. In platelets from mice dosed with ABT-263 in vivo, clopidogrel or deficiency of P2Y(12) receptor enhanced apoptosis along with increased Bak/Bax activation. CONCLUSIONS: This study demonstrates that P2Y(12) activation protects platelets from apoptosis via PI3k-dependent Bak/Bax inactivation, which may be physiologically important to counter the proapoptotic challenge. Our findings that P2Y(12) blockade exaggerates platelet apoptosis induced by ABT-263 (Navitoclax) also imply a novel drug interaction of ABT-263 and P2Y(12) antagonists.

[The inhibition pathway of the EBV-immortalized cells in children with infectious mononucleosis].

OBJECTIVE: To explore the inhibition pathway of the EBV-immortalized cells (CD23(+)) in children with infectious mononucleosis (IM) caused by Epstein-Barr virus. METHODS: The expressions of CD23, CD19, CD95, Bcl-2 and the co-expressions of CD23CD95, CD19CD23 on peripheral blood mononuclear cell (PBMC) were analyzed by flow cytometry (FCM) during acute phase, early convalescent phase and convalescent phase of 34 EBV-IM children and compared with that of 24 healthy donors. RESULTS: (1) The levels of CD23(+) and CD23(+)CD19(+) cells decreased and CD95(+), CD95(+)CD23(+), Bcl-2(+) cells increased markedly in IM patients in acute phase [CD95(+) cells (19.43 +/- 8.46)%; CD95(+)CD23(+) cells (1.81 +/- 1.71)%; Bcl-2(+) cells (23.41 +/- 26.47)%] and early convalescent phase [CD95(+) cells (12.94 +/- 5.05)%; CD95(+)CD23(+) (1.05 +/- 1.20)%; Bcl-2(+) cells (10.54 +/- 9.68)%], as compared with those of healthy controls [CD95(+) cells (10.39 +/- 2.90)%; CD95(+)CD23(+) cells (0.50 +/- 0.46)%; Bcl-2(+) cells (7.25 +/- 2.88)%]. The earlier the course of IM, the more abnormal the expressive levels. All the abnormal results returned to normal in convalescent phase. (2) Positive relationships were observed between the expressions of CD95(+)CD23(+) cells and that of CD23(+) cells, CD23(+)CD19(+) cells during acute and early convalescent phase, the expressions of Bcl-2(+), CD3(+) cells and CD23(+), CD23(+)CD19(+) cells during acute phase, the expressions of CD95(+)CD23(+) cells and Bcl-2(+) cells during acute phase, and the expressions of CD95(+)CD23(+) cells and CD95(+) cells during convalescent phase. CONCLUSION: The results indicate that CD95L-CD95 mediated apoptosis plays an important role in eliminating EBV-immortalized cells, which is counteracted partly by Bcl-2.