Parp As Transcriptional Regulator Of Inflammation And Lymphocyte Homing

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7.2.1 Effect of PARP on the Expression of Chemokines, Adhesion Molecules, Collagenase, MHC-II Molecules, and Inducible Nitric Oxide Synthetase

Migration of inflammatory cells (monocytes, granulocytes, and lymphocytes) to the site of inflammation as well as migration of lymphocytes to lymphoid organs (lymph nodes, Peyer's patches, tonsils) where antigens are presented to lymphocytes by APCs is regulated by chemotactic cytokines called chemokines. Chemokines induce the upregulation of adhesion molecules on the surface of endothelial cells and migrating cells (granulocytes, monocytes, lymphocytes) leading to a firm attachment of migrating cells to the endothelium followed by transendothelial migration. At the site of inflammation, movement of leukocytes in the tissues is enhanced by enzymes such as collagenase, hyaluronidase, and elastase, which degrade the intercellular matrix of the connective tissue. Upon exposure to cytokines, inflammatory cells become activated. Activation results in the upregulation of MHC-II molecules and increased production of inflammatory mediators, e.g., NO. Upregulation of MHC-II molecules on the surface of thyroid cells and synovial cells has been implicated in the pathomechanism of autoimmune inflammation (autoimmune thyroiditis, biliary cirrhosis, type 1 diabetes, arthritis).191-195

PARP may interfere with the sequence of events at several points. PARP has been shown to enhance activator-dependent transcription.60 Moreover, PARP has also been found to act as a coactivator for AP-2-mediated transcriptional activation.61 As synthesis of cytokines and chemokines occurs via activator-dependent transcription of cytokine genes,196-198 the possibility exists that PARP enhances the production of chemokines and cytokines. Indeed, peritoneal macrophages and embryonal fibroblasts from PARP-deficient mice produced significantly less macrophage inflammatory protein-1a (MIP-1a) a CC chemokine known to be responsible for the recruitment of monocytes to inflammatory environment (Virag, Hasko, and Szabo, unpublished observations). In various inflammatory models ranging from zymozan peritonitis to colitis and arthritis, in animals treated with PARP inhibitors as compared with wildtype mice, we have found a reduced number of neutrophil granulocytes as measured by myeloperoxidase activity of tissue lysates.199-201 This reduced migration of neu-trophil granulocytes could be explained by an inhibition by PARP inhibitors of chemokine expression. However, this hypothesis has not yet been tested in these in vivo models. Alternatively, impaired expression of adhesion receptors in the absence of PARP could also be made responsible for the inhibition of granulocyte recruitment. This scenario is supported by findings that human umbilical vein endothelial cells (HUVEC) and fibroblasts respond to cytokines with a reduced expression of intra-cellular adhesion molecule-1 (ICAM-1) and P-selectin.202 Furthermore, a decreased expression of these adhesion molecules has been found in the hearts of PARP-- mice as compared with wild-type (PARP+/+) ones after myocardial ischemia reperfusion.202

Following transmigration through the endothelial layer, inflammatory cells migrate in the connective tissue toward the source of chemokines. Migration in the connective tissue is facilitated by the production of collagenase and other enzymes degrading the components of extracellular matrix. PARP inhibitors have been shown to inhibit collagenase expression in cultured rabbit synovial fibroblasts.203 Thus, the beneficial effect of PARP inhibition in reducing the severity of inflammation may be in part due to inhibition of leukocyte migration in the inflammatory environment. The effect of PARP inhibitors on the expression of other enzymes such as elastase or hyaluronidase involved in the degradation of extracellular matrix has not yet been investigated. Activation of inflammatory cells is accompanied by the upregulation of activation markers (e.g., MHC-II molecules) and the production of inflammatory mediators such as NO. PARP has been shown to be involved in the regulation of both MHC204-205 and iNOS19,206-208 expression.

Based on these findings, we can conclude that PARP inhibitors exert their potent anti-inflammatory effects by a complex mechanism (Figure 7.12) involving cyto-protection from the necrotic effects of ROIs and RNIs, attenuation of endothelial transmigration of inflammatory cells, and inhibition of proinflammatory cytokines, chemokines, and inflammatory mediators.

7.2.2 Effect of PARP on Nuclear Receptor Signaling

As opposed to activator-dependent transcription, which is enhanced, nuclear receptor signaling is suppressed by PARP. This has been demonstrated by Miyamoto et al.,209 who showed that PARP bound directly to retinoid X receptor (RXR) and repressed socinrxm:

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