Inhibitors of poly(ADP‐ribose) polymerase‐1 suppress transcriptional activation in lymphocytes and ameliorate autoimmune encephalomyelitis in rats

Abstract

1 In the presence of genotoxic stress poly(ADP-ribose) polymerase-1 (PARP-1) leads to NAD + and ATP depletion, participating in the pathogenesis of several disorders including in¯ammation. Accordingly, chemical inhibitors of PARP-1 are e cacious anti-in¯ammatories, albeit the underlying molecular mechanisms are still under debate. 2 This study investigated the e ect of the PARP-1 inhibitors 6(5H)-phenanthridinone and benzamide as well as that of benzoic acid, an inactive analogue of benzamide, on development of experimental allergic encephalomyelitis (EAE) in rats. Both 6(5H)-phenanthridinone and benzamide attenuated development of EAE, reducing clinical score, neuroimmune in®ltration and expression of in¯ammatory mediators such as inducible nitric oxide synthase, interleukin-1b and -2, cyclooxygenase-2, tumour necrosis factor-a and interferon-g in the spinal cord of myelin-immunized rats. Importantly, no evidence of NAD + and ATP depletion as well as poly(ADP-ribose) formation was detected in the spinal cord.3 By contrast, a robust formation of poly(ADP-ribose) occurred in B-and T-cell areas in lymph nodes of myelin-immunized rats and was suppressed by the treatment with 6(5H)-phenanthridinone and benzamide. In cultures of activated rat lymphocytes, 6(5H)-phenanthridinone and benzamide reduced the DNA-binding activity of NF-kB and AP-1 and transcription of pro-in¯ammatory cytokines such as interleukin-2, interferon-g and tumour necrosis factor-a. 4 Notably, benzoic acid did not reproduce the in vivo and in vitro e ects of its parent compound. 5 These ®ndings indicate that PARP-1 promotes transcriptional activation in lymphocytes and inhibitors of its enzymatic activity are useful for the treatment of autoimmune disorders of the central nervous system.

A Key Role for Poly(ADP-Ribose) Polymerase-1 Activity during Human Dendritic Cell Maturation

“…Hence, data lend support to the hypothesis that PARP-1 inhibitors compromise the T cell stimulatory capacity of DCs. The present findings, along with evidence that suppression of PAR formation also affects immunocompetence of T and B lymphocytes (6,13,14), help to explain why inhibitors of PARP-1 exert widespread immunosuppression (65). Finally, although the effects of PARP-1 inhibitors on DCs in vivo remains to be evaluated, we infer that these compounds, currently tested in different clinical trials in humans (66), can be harnessed to develop innovative therapies aimed at promoting graft survival or combating autoimmune disorders.…”

“…Specifically, the enzyme positively regulates activation of macrophages (8,9,35), microglia (7,36), granulocytes (37), lymphocytes (6,13,14), as well as TNF-␣-challenged endothelial cells (38). Also, parp-1 null mice are resistant to endotoxic shock (39), and PARP-1 inhibitors provide protection in models of pleuritis (40), arthritis (41), asthma (42), colitis (43,44), allergic encephalomyelitis (6,15,45), and other autoimmune disorders (46). In this context, the present findings point to the negative regulation of DCs by PARP-1 inhibitors as a key mechanism through which this class of drugs suppresses the inflammatory response.…”

“…In particular, numerous reports demonstrate that PARP-1 and PAR formation positively regulate transcription in several types of immune cells (4 -7), as well as macrophage activation (8,9), granulocyte migration (10,11), and T cell proliferation (6,12,13). Also, PARP-1 inhibition increases Ab class-switching (14), and alters Ab production during the autoimmune response in the CNS (15).…”

Increased Foxp3+ Regulatory T Cells in Poly(ADP-Ribose) Polymerase-1 Deficiency

“…However, growing evidence is revealing that polyADPribosylation also plays a key role in the regulation of gene transcription independently from DNA damage. Several reports demonstrated that PARP-1 regulates gene transcription in several types of immune cells (3), including dendritic cells (4) and macrophages (5). Inhibition of PARP-1 activity reduces the secretion of proinflammatory cytokines (3).…”

Regulation of Interleukin-10 Gene Expression in Macrophages Engulfing Apoptotic Cells

“…Pbx-1a and Pbx-1b are the 2 isoforms of Pbx-1. Pbx-1a expression is restricted to neural tissues while Pbx-1b exhibits widespread expression patterns in the mouse embryo (Moens and Selleri encephalomyelitis (EAE) (Chiarugi 2002), diabetes mellitus (Akiyama and others 2001). Furthermore, PARP −/− mice are protected from endotoxic shock (Kühnle and others 1999;Oliver and others 1999).…”