Anti-apoptotic genes in the survival of monocytic cells during infection

Abstract

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.

Keywords: Apoptosis; HIV; anti-apoptotic genes; monocytes/macrophages; tuberculosis..

Fig. (1)

Overview of apoptosis and the main anti-apoptotic molecules: Binding of death receptors (Fas, TNF-R, TRAIL-R) to their ligands (Fas-L, TNF, TRAIL) initiates the extrinsic apoptotic pathway. Association of adaptor molecules (FADD - Fas-associated death domain protein, TRADD–TNF receptor associated death domain protein) induces the formation of DISC (death inducing signaling complex), which activates caspase 8 and subsequently caspase 3. FLIP is the main anti-apoptotic molecule of this pathway, as it prevents caspase 8 activation. Release of cytochrome c from the mitochondria in response to cellular stress initiates the intrinsic apoptotic pathway. Cytochrome c associates with Apaf-1 and procaspase 9 to form the apoptosome, a multimeric protein complex that induces cleavage of inactive caspase 9 to its active form. Both pathways converge with activation of caspase 3, the main effector caspase. The two pathways are also connected by the ability of active caspase 8 to activate Bid (BH3-interacting domain death agonist) – tBid (truncated Bid) is a proapoptotic molecule that can induce release of cytochrome c from the mitochondria and thus initiate the intrinsic pathway. The two main antiapoptotic families are Bcl2 and IAPs. Anti-apoptotic Bcl2 members maintain mitochondrial integrity, while IAP can inactivate caspases. IAP activity is antagonized by Smac (also known as Diablo), a proapoptotic molecule released from the mitochondria [1, 9, 12].