Poly(ADP-ribosylation) is a post-translational modification of nuclear proteins in response to DNA damage that activates the base excision repair machinery. Poly(ADP-ribose) polymerase which we will now call PARP-1, has been the only known enzyme of this type for over 30 years. Here, we describe a cDNA encoding a 62-kDa protein that shares considerable homology with the catalytic domain of PARP-1 and also contains a basic DNA-binding domain. We propose to call this enzyme poly(ADP-ribose) polymerase 2 (PARP-2). The PARP-2 gene maps to chromosome 14C1 and 14q11.2 in mouse and human, respectively. Purified recombinant mouse PARP-2 is a damaged DNA-binding protein in vitro and catalyzes the formation of poly(ADP-ribose) polymers in a DNA-dependent manner. PARP-2 displays automodification properties similar to PARP-1. The protein is localized in the nucleusin vivo and may account for the residual poly(ADP-ribose) synthesis observed in PARP-1-deficient cells, treated with alkylating agents or hydrogen peroxide.

Poly (ADP‐ribose) polymerase‐1 is a nuclear DNA‐binding protein that participates in the DNA base excision repair pathway in response to genotoxic stress in mammalian cells. Here we show that PARP‐1 ‐deficient cells are defective in NF‐κB‐dependent transcription activation, but not in its nuclear translocation, in response to TNF‐α. Treating mice with lipopolysaccharide (LPS) resulted in the rapid activation of NF‐κB in macrophages from PARP‐1+/+ but not from PARP‐1−/− mice. PARP‐1 ‐deficient mice were extremely resistant to LPS‐induced endotoxic shock. The molecular basis for this resistance relies on an almost complete abrogation of NF‐κB‐dependent accumulation of TNF‐α in the serum and a down‐regulation of inducible nitric oxide synthase (iNOS), leading to decreased NO synthesis, which is the main source of free radical generation during inflammation. These results demonstrate a functional association in vivo between PARP‐1 and NF‐κB, with consequences for the transcriptional activation of NF‐κB and a systemic inflammatory process.

Poly (ADP-ribose) polymerase is a zinc-finger DNA-binding enzyme which detects and signals DNA strand breaks generated either directly during base excision repair, or indirectly by genotoxic agents such as oxygen radicals. In response to genotoxic injury, PARP catalyses the synthesis of poly (ADP-ribose), from its substrate β-NAD+ and this polymer is covalently attached to several nuclear proteins and PARP itself. As a result, PARP converts DNA breaks into intracellular signals which activate DNA repair programs or cell death options. Several studies have also shown that PARP is involved in either necrosis and subsequent inflammation or apoptosis. Although this enzyme is not indispensable during the latter cell death program, it has been demonstrated that PARP plays a facilitating role in this process. PARP is activated at an intermediate stage of apoptosis and is then cleaved and inactivated at a late stage by apoptotic proteases, namely caspase-3 / CPP-32 / Yama / apopain and caspase-7. This cleavage prevents necrosis during apoptosis, avoiding inflammation. All these functions, and the observation that PARP is an abundant and highly conserved enzyme, suggest that this enzyme plays a pivotal role, particularly in the maintenance of genomic DNA stability, apoptosis and in the response to oxidative stress. Since these situations are found in cancer, inflammation, autoimmunity (such as diabetes), myocardial dysfunction, certain infections, ageing and radiation / chemical exposure, attempts have been made to modulate PARP activity. With regard to the increasing interest towards PARP, the aim of this review is to explain the cellular role of PARP and the advantages of modulating its activity in diverse preventive or therapeutic strategies.

Objective: The rationale for blocking interleukin‐6 (IL‐6) in rheumatoid arthritis (RA) lies chiefly in the proinflammatory effect of this cytokine. Few studies have evaluated the consequences of anti–IL‐6 receptor (IL‐6R) antibody treatment on Treg cells. This study was undertaken to elucidate the mechanism of action of anti–IL‐6R antibody treatment by studying the effects on Treg cells in an experimental arthritis model and in patients with RA.Methods: Mice with collagen‐induced arthritis (CIA) were treated with a mouse anti–IL‐6R antibody (MR16‐1), and changes in Treg, Th1, and Th17 cells were assessed at key time points during the course of the disease. Peripheral blood from 15 RA patients was collected on day 0 and after 3 months of tocilizumab treatment for flow cytometry analysis of Th17 and Treg cells.Results: In MR16‐1–treated mice, Th17 cell frequencies were unchanged, whereas Treg cell frequencies were increased. The Treg cell phenotype showed marked changes, with an increase in the frequency of CD39+ Treg cells in the lymph nodes and spleen. Interestingly, similar CD39+ Treg cell expansion was observed in RA patients who were tocilizumab responders at 3 months, with no change in Th17 cell frequency. Moreover, fluorescence‐activated cell–sorted CD39+ Treg cells from responder RA patients were functionally able to suppress the proliferation of conventional T cells.Conclusion: In both CIA and RA, the frequency of functionally suppressive CD39+ Treg cells is increased as a result of anti–IL‐6R treatment, whereas Th17 cells are unaffected. The modification of Treg cell frequency and phenotype may be one of the mechanisms involved in the therapeutic effect of IL‐6 blockade in RA.

Reciprocal interactions between NK cells and dendritic cells have been shown to influence activation of NK cells, maturation, or lysis of dendritic cells and subsequent adaptive immune responses. However, little is known about the crosstalk between monocytes and NK cells and the receptors involved in this interaction. We report in this study that human monocytes, upon TLR triggering, up-regulate MHC class I-Related Chain (MIC) A, but not other ligands for the activating immunoreceptor NKG2D like MICB or UL-16 binding proteins 1–3. MICA expression was associated with CD80, MHC class I and MHC class II up-regulation, secretion of proinflammatory cytokines, and apoptosis inhibition, but was not accompanied by release of MIC molecules in soluble form. TLR-induced MICA on the monocyte cell surface was detected by autologous NK cells as revealed by NKG2D down-regulation. Although MICA expression did not render monocytes susceptible for NK cell cytotoxicity, LPS-treated monocytes stimulated IFN-γ production of activated NK cells which was substantially dependent on MICA-NKG2D interaction. No enhanced NK cell proliferation or cytotoxicity against third-party target cells was observed after stimulation of NK cells with LPS-activated monocytes. Our data indicate that MICA-NKG2D interaction constitutes a mechanism by which monocytes and NK cells as an early source of IFN-γ may communicate directly during an innate immune response to infections in humans.