An unexpected finding of HDAC inhibitors was the reduction in disease severity of models of murine autoimmune disease. The mouse model for systemic lupus erythematosus is the lpr/lpr mouse that develops a spontaneous disease characterized by nephritis, proteinuria and early death. Trichostatin A was injected into these mice before the onset of significant disease for 5 weeks. Because trichostatin A in water is insoluble, the vehicle was also used for 5 weeks of treatment. Trichostatin A treatment resulted in significantly less proteinuria; in addition, there was histolog-
ical evidence of decreased glomerulonephritis (Mishra et al. 2003), as well as a reduction in spleen weight. A concomitant decreased expression of steady state levels of mRNA for IL-12, IFNy, IL-6, and IL-10 was observed as well as protein levels for these cytokines. Not unexpected, total cellular chromatin contained an accumulation of acetylated histones H3 and H4.
These mouse studies were consistent with a similar effect of tricho-statin A in peripheral T cells from patients with systemic lupus erythe-matosus (Mishra et al. 2001). In T-helper cells from patients with the disease, there is overexpression of the T-helper 2 cytokine IL-10 and the pro-inflammatory cytokine CD40 ligand (also known as CD154). However, incubation of the cells from these patients with trichostatin A decreased spontaneous IL-10 and CD40 ligand. As a consequence of decreased IL-10, there was an increase in IFNy production. Further studies in the lpr/lpr mouse model were carried out using the water-soluble SAHA compound. SAHA was injected into lpr/lpr mice from age 10-20 weeks. Although this treatment did not affect the level of auto-antibodies that develop in these mice and although the deposition of anti-glomerular immunoglobulin was unaffected by SAHA treatment, there was a marked reduction in the histological abnormalities of the kidneys and a decrease in the proteinura (Reilly et al. 2004). In addition, spleen weight was decreased as well as fewer CD4-CD8 cells, both pathological indicators for the disease. Mesangial cells from mice treated with SAHA, when stimulated with LPS plus IFNy, produced less spontaneous nitric oxide (Reilly et al. 2004).
IFNy is an important cytokine in several autoimmune diseases but is of particular importance in the pathogenesis of lupus erythematosus. The animal model for this disease is the lpr/lpr mouse, which develops a spontaneous proteinuria and lethal nephritis. Neutralization of IL-18 reduced the proteinuria and decreased the lethality (Bossu et al. 2003). In human PBMCs, SAHA reduces IFNy induced by endotoxin or by the combination of IL-12 plus IL-18 (Leoni et al. 2002). Although there was an increase in IFNy production in T cells from lupus patients exposed to trichostatin (Mishra et al. 2001), the effect was most likely due to a reduction in IL-10.
Relevant to the issue of HDAC inhibition of IFNy production is the mouse model of graft-versus-host disease (GVHD), a model for GVHD in humans following bone marrow transplantation. GVHD and leukemic relapse are the two major obstacles to successful outcomes after allo-geneic bone marrow transplantation. Human and mouse studies have demonstrated dysregulation of proinflammatory cytokines with the loss of gastrointestinal tract integrity contributing to GVHD. In mice with acute GVHD, the administration of SAHA at low doses reduced IFNy, TNFa, IL-1P and IL-6 production (Reddy et al. 2004). In addition, intestinal histopathology, clinical severity, and mortality were reduced compared with vehicle-treated animals (Reddy et al. 2004). However, SAHA did not impair graft versus leukemia responses and significantly improved leukemia-free survival by using two different tumors (Reddy et al. 2004). These findings are consistent with the ability of SAHA to suppress LPS-induced TNFa and IFNy as well as IL-12/IL-18-induced IFNy and IL-6, but also with the failure of SAHA to reduce IFNy and other cytokines stimulated by anti-CD3 agonistic antibodies.
The therapeutic benefit of blocking pro-inflammatory cytokines in the progression of rheumatoid arthritis has been based on models of the disease in mice and rats. Two models have been used: collagen-induced arthritis and adjuvant arthritis. In the latter, the pathological effects are the destruction of bone and cartilage. The role of cytokines in this process is well established. For example, IL-1P and IL-18 are potent inducers of metalloproteinases and inhibitors of proteoglycan synthesis (Bakker etal. 1997; Joosten et al. 2003; van den Berg et al. 1994). Using the model of rat adjuvant arthritis, treatment with phenylbutyrate or trichostatin A resulted in decreased expression of TNFa (Chung et al. 2003). This was associated with a decrease in joint swelling, synovial mononuclear cell infiltration, synovial hyperplasia, and pannus formation. There was also a remarkable absence of cartilage or bone destruction, commonly observed in adjuvant arthritis (Chung et al. 2003).
The HDAC inhibitor depsipeptide (FK228) was used to treat mice using a model of rheumatoid arthritis induced by autoantibody. Following the establishment of the arthritis, mice were injected intravenously with 2.5mg/kg and clinical scores were obtained. A single dose injection of FK228 reduced joint swelling, synovial cell infiltration and also decreased bone and cartilage destruction (Nishida et al. 2004). There was a reduction in TNFa and IL-1|3 production associated with histone hy-peracetylation in the synovial cells. However, at the doses used, FK228 inhibited the in vitro proliferation of synovial fibroblasts, by a mechanism that may result in arrest of cell cycle. Indeed, FK228 increased acetylation of p21 in synovial cells (Nishida et al. 2004). An important concept is that inhibitors of HDAC at high doses act as anti-proliferative agents and must be distinguished from a purely anti-cytokine effect.
The in vivo model of ConA-induced hepatic injury, a model that is TNFa- and IL-18-dependent, is a model of activated CD4+ T cells that may represent autoimmune hepatitis and possibly most cytokine-mediated hepatic injury (Faggioni et al. 2000; Fantuzzi et al. 2003). In this model, a single dose of 50 mg/kg SAHA given orally reduced the injury by more than 70% as determined by a reduction in circulating levels of ALT by (Leoni et al. 2002).
3.3 Reducing Cytokines by HDAC Inhibitors
3.3.1 Low Concentrations of HDAC Inhibitors are Anti-inflammatory Whereas High Concentrations are Needed for Anti-tumor Effects
It is interesting to note that the inhibitory effect of SAHA appears to be particularly effective for reducing proinflammatory cytokines at relatively lower doses compared to the doses used for inhibition of tumors. In fact, the in vitro concentrations of SAHA that inhibited proliferation of tumor cell lines by 50% were 1-5 ^M (Leoni et al. 2002), similar to those described by others (Butler et al. 2000). However, at nanomolar concentrations (50-200 nM), a 50%-85% reductions in LPS-induced secretion of TNFa, IL-1p, IFNy, and IL-12 in freshly isolated human PBMCs was reported (Leoni et al. 2002). Similar to the reduction in protein levels of TNFa and IFNy, the steady state mRNA levels for these two cytokines were reduced, particularly those of IFNy. In addition, the in vitro production of nitric oxide in primary mouse peritoneal macrophages stimulated with the combination of TNFa and IFNy was suppressed by SAHA at 200-400 nM (Leoni et al. 2002). Therefore, the anti-inflammatory effect of SAHA is evident at concentrations lower than those needed to suppress tumor cell growth in vitro and in vivo.
IFNy production triggered by the T-cell receptor using anti-CD3 was unaffected by SAHA (Leoni et al. 2002). In contrast, when stimulated by either LPS or the combination of IL-18 plus IL-12, IFNy production was markedly reduced by SAHA. The intracellular and extracellular levels of the anti-inflammatory cytokine IL-1 receptor antagonist were unaffected by SAHA in LPS-stimulated human PBMCs and there was no reduction in circulating IL-10 levels in mice injected with LPS. SAHA also did not reduce the production of the proinflammatory chemokine IL-8. Consistent with this finding, steady-state mRNA for IL-8 was unaffected by SAHA (Leoni et al. 2002).
Pretreatment with SAHA resulted in reduced secretion of mature IL-1|3 from PBMCs and the level of circulating IL-1p in LPS-injected mice (Leoni et al. 2002). However, SAHA did not affect steady state levels of IL-1P mRNA or the intracellular levels of precursor IL-1p. In the same PBMC cultures, SAHA reduced both the secretion of TNFa and IFNy as well as their mRNA levels. Therefore, the reduction in IL-1|3 by SAHA appears to be primarily at the level of secretion of mature IL-1 p. Although the pathway(s) for secretion of IL-1p remains unclear, there is no dearth of evidence that inhibition of caspase-1 results in decreased secretion of mature IL-1P, particularly in LPS-stimulated human monocytes (reviewed in Dinarello 1996). When tested, SAHA at concentrations as high as 10 ^M did not inhibit casapse-1 enzymatic activity. However, SAHA may increase gene expression and synthesis of the intracellular inhibitor of ICE, serpin proteinase inhibitor 9 (Young et al. 2000).
Butyrate reduces IL-12 production but upregulates IL-10 in human blood monocytes (Saemann et al. 2000), although millimolar concentrations are needed. Butyrate also inhibits the proliferation of the Caco-2 colon cancer epithelial cells and reduces spontaneous gene expression of IL-8 in these cells (Huang et al. 1997). Using the same cell line, others have reported that butyrate or trichostatin increase IL-8 production (Fusunyan et al. 1999). It is not uncommon for trichostatin and butyrate to have paradoxical effects on IL-8 production by Caco-2 cells; this is likely due to the state of cell activation. For example, IL-8 secretion was increased by 145% by trichostatin and butyrate alone, whereas in TNFa-stimulated cells IL-8 was inhibited to levels below unstimulated levels (Gibson et al. 1999).
In PBMCs from healthy subjects stimulated with LPS or the combination of IL-12/IL-18 in vitro, there is a consistently observed marked reduction in gene expression and synthesis of IFNy by SAHA. Other investigators have reported that at apoptosis-inducing concentrations of trichostatin and butyrate, IFNy production in T lymphocytes is reduced (Dangond and Gullans 1998). In addition, butyrate or trichostatin inhibited IL-1^-dependent induction of the acute phase protein gene haptoglobin as well as the binding of transcription factors to the hap-toglobin promoter (Desilets et al. 2000). Butyrate and trichostatin also suppress IL-2 induction of c-myc, bag-1, and LC-PTP gene expression (Koyama et al. 2000). The IL-2 enhancer and promoter were suppressed by trichostatin by 50% at 73 nM, whereas at the same concentration there was increased expression directed by the c-fos enhancer and promoter (Takahashi et al. 1996).
Most in vitro studies on inhibitors of HDAC have been carried out using cell lines, particularly cell lines of malignant origin. In contrast, the effects of HDAC inhibitors on primary cells or in vivo studies are more likely to be applied to clinical uses of the agents to treat inflammatory and autoimmune diseases. Diseases of auto-immune/inflammatory nature have altered gene expression profiles as compared to health, and thus one must look at the effect of HDAC inhibitors in stimulated cells rather than resting cells. In the absence of exogenous stimuli, SAHA has no effect on the production of cytokines and steady-state mRNA
levels of cytokines are unaffected (Leoni et al. 2002). In contrast, LPS-induced TNFa and IFNy mRNA were decreased by treatment with SAHA. Therefore, the anti-inflammatory effects of SAHA and possibly other inhibitors of HDAC is selective and likely dependent on the level of activation, particularly in primary cells. Alternatively, SAHA may have anti-inflammatory properties independent of its ability to inhibit nuclear HDAC, for example, hyperacetylation of nonhistone proteins such as ribosomal S3 or the Rel A subunit of NFkB (Takahashi et al. 1996).
LPS-induced circulating TNFa and IL-1^, as well as IFNy, were suppressed by SAHA (Leoni et al. 2002). The use of LPS as an inducer of cytokines is widely accepted as a model of disease. However, with the exception of inflammatory bowel disease, most cytokine-mediated autoimmune diseases are triggered by nonmicrobial products such as autoantibodies and several endogenous cytokines themselves, particularly CD4+ T cell products. IL-12 and IL-18 are primarily macrophage products, which in turn stimulate T lymphocytes to produce IFNy and IL-6. SAHA reduces both LPS- as well as IL-12/IL-18-induced IFNy and IL-6. IL-6 is an important mediator of inflammation, primarily as a B-cell growth factor and an inducer of hepatic acute-phase protein synthesis in diseases such a multiple myeloma (Lust and Donovan 1999), and antibodies to the IL-6 receptor are used to treat multiple myeloma, rheumatoid arthritis, and other autoimmune diseases (Iwamoto et al. 2002). Gene expression for IFNy in resting PBMCs stimulated with LPS was nearly completely absent 24 h after treatment with SAHA. However, either in vitro or in vivo, direct stimulation of T-cell receptor using agonistic anti-CD3-induced IFNy was unaffected by SAHA (Leoni et al. 2002). It appears that IL-12/IL-18 induces IFNy via a pathway, which is sensitive to inhibition by SAHA, whereas the pathway for IFNy via the T-cell receptor is not.
3.4 Mechanism of Action of HDAC Inhibition in Reducing Inflammation
It is important to distinguish between the effects of HDAC inhibition on cytokine production in transformed cell lines with those in primary cells or effects in vivo. Of the several genes coding for the different isoforms of HDAC, HDAC3, a Class I deacetylase, has been studied for its effects on the transcription of TNFa. Overexpression of HDAC3 reduced the ability of the p65 component of NFkB to transcribe the TNFa gene (Miao et al. 2004), whereas inhibition of HDAC, in this particular model, stimulated TNFa expression. Others have reported that HDAC3 associates with a nonhistone substrate, acetylated RelA (p65) and deacetylates the molecule (Chen et al. 2001). In doing so, acetylation/deacetylation of p65 controls the transcriptional responses by affecting the binding to inhibitory kB (Chen et al. 2001). Nonhistone interaction of HDAC3 has been described with mitogen activated protein kinase (MAPK) 11 (Mahlknecht et al. 2004), in which the deacetylation of this kinase prevents activation of MAPK11 (also known as MAPK p38) participation in LPS-induced gene expression. Inhibition of phos-phorylation of MAPK11 prevents transcription of TNFa and other proinflammatory cytokines by blocking the binding of activating transcription factor-2 (ATF-2). It was demonstrated that overexpression of HDAC3 suppresses LPS-induction of TNF gene expression (Mahlknecht et al. 2004). Not unexpectedly, it was shown that inhibition of trichostatin A overcomes the deacetylation by HDAC3 and increases the production of TNFa in LPS-stimulated macrophage cell lines (Mahlknecht et al. 2004).
Also in macrophage cell lines, TNFa production is increased upon inhibition of HDAC (Lee et al. 2003) due to acetylation of H3 and H4. In primary monocytes, it is only upon maturation during 7 days of culture that a similar acetylation takes place and increased expression of TNFa is observed (Lee et al. 2003). The inhibition of TNFa production by p50 homodimers binding to the TNFa promoters is well established. However, this inhibition is reversed by HDAC inhibition and increased TNFa is observed (Wessells et al. 2004). In order to resolve the discrepancies between increased or decreased TNFa production by inhibition of HDAC, one may conclude that in cell lines increases in TNFa produc tion are consistently observed and may be due to acetylation of cellular proteins or nuclear histone. On the other hand, inhibition of TNFa gene expression or synthesis by SAHA is consistently observed in primary cells in vitro and in vivo models of disease.
Clearly, from the present studies and also from previous reports (Mishra et al. 2003), inhibition of HDAC3 is not a likely target of SAHA at concentrations that suppress cytokines. The treatment of lupus-prone mice with trichostatin A reduced proteinuria, the infiltration of destructive inflammatory cells into the glomerulus, and reduced spleen weight (Mishra et al. 2003). The clinical benefit of trichostatin A in these mice was associated with decreases in IL-12, IFNy, and IL-6. The evidence that SAHA primarily suppresses inflammation in animal models of disease (Leoni et al. 2002; Mishra et al. 2003; Reddy et al. 2001; Reilly et al. 2004) via suppression of TNFa, IL-1|3, IFNy, and IL-6 transcription is consistent with a histone rather than a nonhistone target for hyperacetylation in primary cells.
Acknowledgements. These studies are supported by NIH Grants AI-15614 and HL-68743 and the Colorado Cancer Center
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