Monocytic cells survive HIV replication and consequent cytopathic effects because of their decreased sensitivity to HIV-induced apoptosis. However, the mechanism underlying this resistance to apoptosis remains poorly understood. Lymphocytic cells are exposed to microbial products because of their translocation from the gut in persons with chronic HIV infections or following coinfections. We hypothesized that activation of monocytic cells by such microbial products through interaction with corresponding TLRs may confer antiapoptotic signals. Using HIV-viral protein R (Vpr)(52–96) peptide as a model apoptosis-inducing agent, we demonstrated that unlike monocyte-derived macrophages, undifferentiated primary human monocytes and promonocytic THP-1 cells are highly susceptible to Vpr(52–96)-induced apoptosis. Interestingly, monocytes and THP-1 cells stimulated with TLR9 agonist CpG induced almost complete resistance to Vpr(52–96)-induced apoptosis, albeit through a TLR9-independent signaling pathway. Moreover, CpG selectively induced the antiapoptotic cellular inhibitor of apoptosis (c-IAP)-2 protein and inhibition of the c-IAP-2 gene by either specific small interfering RNA or synthetic second mitochondrial activator of caspases mimetic reversed CpG-induced resistance against Vpr(52–96)-mediated apoptosis. We demonstrated that c-IAP-2 is regulated by the JNK and calcium signaling pathway, in particular calmodulin-dependent protein kinase-II. Furthermore, inhibition of JNK and the calcium signaling including the calmodulin-dependent protein kinase-II by either pharmacological inhibitors or their specific small interfering RNAs reversed CpG-induced protection against Vpr(52–96)-mediated apoptosis. We also show that CpG induced JNK phosphorylation through activation of the calcium signaling pathway. Taken together, our results suggest that CpG-induced protection may be mediated by c-IAP-2 through the calcium-activated JNK pathway via what appeared to be TLR9-independent signaling pathways.
The objective of this study was to define whether IL-6 is an early marker of infection in the newborn. To correlate the occurrence of clinical chorioamnionitis with the levels of IL-6 expression in neonates, IL-6 was measured in cord plasma by ELISA and in mononuclear cells by reverse transcriptase-PCR before and after mitogenic stimulation. Eight neonates were included in each of the following four groups: elective cesarean section, uncomplicated normal spontaneous vaginal delivery, delivery after prolonged rupture of amniotic membranes with no evidence of chorioamnionitis, and delivery with evidence of chorioamnionitis. All 32 neonates were clinically well after delivery, and all 16 babies with prolonged rupture of membranes or clinical chorioamnionitis had negative blood cultures. Elevated IL-6 levels were found only in neonates born to mothers with chorioamnionitis (119.7 +/- 33.5 pg/mL versus 2.71 +/- 0.59 pg/mL, p < 0.005). Mononuclear cells from five of these neonates expressed no IL-6 mRNA in vivo despite elevated levels of IL-6 in their cord plasma. Cord blood mononuclear cells from healthy term babies were capable of synthesizing IL-6 in vitro in response to stimulation with bacterial lipopolysaccharide. These results suggest that IL-6 levels in cord plasma increased with clinical chorioamnionitis, despite the lack of evidence of infection in the neonates. Therefore, we conclude that, although a high level of IL-6 may be a good marker of chorioamnionitis, it may not be a specific marker of infection in the newborn.
Macrophages are cells of the immune system that protect organisms against invading pathogens by fulfilling critical roles in innate and adaptive immunity and inflammation. They originate from circulating monocytes and show a high degree of heterogeneity, which reflects the specialization of function given by different anatomical locations. Differentiation of monocytes towards a macrophage phenotype is also accompanied by an increase of resistance against various apoptotic stimuli, a required characteristic that allows macrophages to accomplish their function in a stressful environment.Apoptosis, a form of programmed cell death, is a tightly regulated process, needed to maintain homeostasis by balancing proliferation with cellular demise. Caspases, a family of cysteine proteases that are highly conserved in multicellular organisms, function as central regulators of apoptosis. FLIP (FLICE-inhibitory protein), anti-apoptotic members of the Bcl2 family and inhibitors of apoptosis (IAP) are the main three groups of anti-apoptotic genes that counteract caspase activation through both the extrinsic and intrinsic apoptotic pathways.Modulation of the apoptotic machinery during viral and bacterial infections, as well as in various malignancies, is a wellestablished mechanism that promotes the survival of affected cells. The involvement of anti-apoptotic genes in the survival of monocytes/macrophages, either physiological or pathological, will be described in this review. How viral and bacterial infections that target cells of the monocytic lineage affect the expression of anti-apoptotic genes is important in understanding the pathological mechanisms that lead to manifested disease. The latest therapeutic approaches that target anti-apoptotic genes will also be discussed.
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