In the past decade, a new family of highly conserved antioxidant enzymes, Peroxiredoxins (Prxs), have been discovered and defined. There are two major Prx subfamilies: one subfamily uses two conserved cysteines (2-Cys) and the other uses 1-Cys to scavenge reactive oxygen species (ROS). This review focuses on the four mammalian 2-Cys members (Prx I-IV) that utilize thioredoxin as the electron donor for antioxidation. The array of biological activities of these proteins suggests that they may be evolutionarily important for cell function. For example, Prxs are capable of protecting cells from ROS insult and regulating the signal transduction pathways that utilize c-Abl, caspases, nuclear factor-kappaB (NF-kappaB) and activator protein-1 (AP-1) to influence cell growth and apoptosis. Prxs are also essential for red blood cell (RBC) differentiation and are capable of inhibiting human immunodeficiency virus (HIV) infection and organ transplant rejection. Distribution patterns indicate that Prxs are highly expressed in the tissues and cells at risk for diseases related to ROS toxicity, such as Alzheimer's and Parkinson's diseases and atherosclerosis. This interesting correlation suggests that Prxs are protective against ROS toxicity, yet overwhelmed by oxidative stress in some cells. Prxs tend to form large aggregates at high concentrations, a feature that may interfere with their normal protective function or may even render them cytotoxic. Imbalance in the expression of subtypes can also potentially increase their susceptibility to oxidative stress. Understanding the function and biological role of Prxs may lead to important discoveries about the cellular dysfunction of ROS-related diseases ranging from atherosclerosis to cancer to neurodegenerative diseases.

CD8؉ T-cells are a major source for the production of non-cytolytic factors that inhibit HIV-1 replication. In order to characterize further these factors, we analyzed gene expression profiles of activated CD8؉ T-cells using a human cDNA expression array containing 588 human cDNAs. mRNA for the chemokine I-309 (CCL1), the cytokines granulocyte-macrophage colony-stimulating factor and interleukin-13, and natural killer cell enhancing factors (

A cytosol factor from human red blood cells enhances natural killer (NK) activity. This factor, termed NK-enhancing factor (NKEF), is a protein of 44,000 M(r) consisting of two subunits of equal size linked by disulfide bonds. NKEF is expressed in the NK-sensitive erythroleukemic cell line K562. Using an antibody specific for NKEF as a probe for immunoblot screening, we isolated several clones from a lambda gt11 cDNA library of K562. Additional subcloning and sequencing revealed that the candidate NKEF cDNAs fell into one of two catagories of closely related but non-identical genes, referred to as NKEF A and B. They are 88% identical in amino acid sequence and 71% identical in nucleotide sequence. Southern blot analysis suggests that there are two to three NKEF family members in the genome. Analysis of predicted amino acid sequences indicates that both NKEF A and B are cytosol proteins with several phosphorylation sites each, but that they have no glycosylation sites. They are significantly homologous to several other proteins from a wide variety of organisms ranging from prokaryotes to mammals, especially with regard to several well-conserved motifs within the amino acid sequences. The biological functions of these proteins in other species are mostly unknown, but some of them were reported to be induced by oxidative stress. Therefore, as well as for immunoregulation of NK activity, NKEF may be important for cells in coping with oxidative insults.

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Natural killer (NK) and lymphokine-activated killer (LAK) cell cytotoxic functions can be strongly augmented by the iron-carrier protein lactoferrin (LF). LF significantly enhances NK and LAK activities when added at the beginning of NK or LAK cytotoxicity assays. LF is effective in augmenting cytotoxic activities at concentrations as low as 0.75 microgram/ml, and higher concentrations of LF induce greater augmentation of NK and LAK. Iron does not appear to be essential for LF to increase NK and LAK, as depleting iron from LF with the chelator deferoxamine does not affect the capacity of LF to increase cytotoxicity. LF is known to have RNase enzymatic activity, and LF enhancement of NK and LAK can be blocked by RNA. However, LFs from two different sources with over 100-fold difference in RNase activity are equally effective in enhancing NK and LAK. Furthermore, purified non-LF RNase does not modulate NK or LAK activity and DNA is as effective as RNA in blocking LF augmentation of NK or LAK cytotoxicity. Therefore, the RNase activity is unlikely to be responsible for LF enhancement of the cytotoxicities. Newborn infants are known to have low NK activity and NK and LAK cells have been implicated in host defense against microbial infections. Thus, maternal milk-derived LF may have a role in boosting antimicrobial immunity in the early stages of life. In adults, LF released from neutrophils may enhance NK and LAK functions in the inflammatory process induced by microbial infections.