Role of the proteasome and NF-κB in streptococcal cell wall-induced polyarthritis

Palombella, Vito J.; Conner, Elaine M.; Fuseler, John W.; Destree, Antonia T.; Davis, Jonathan M.; Laroux, F. Stephen; Wolf, Robert; Huang, Jinlong; Brand, Stephen; Elliott, Peter J.; Lazarus, Douglas; McCormack, Teresa A.; Parent, Lana; Stein, Ross L.; Adams, Julian; Grisham, Matthew B.

doi:10.1073/pnas.95.26.15671

Cited by 273 publications

(195 citation statements)

References 46 publications

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“…route, but this drug has been shown to be active also orally. 13,27 MLN273 is another compound that inhibits the proteasomal activity, and similarly to Velcade, it is a selective, potent, and reversible boronic acid analogue. Millennium Pharmaceuticals is currently testing MLN273 in preclinical studies, in a different area than cancer.…”

Section: Discussionmentioning

confidence: 99%

Localized Treatment with a Novel FDA-Approved Proteasome Inhibitor Blocks the Degradation of Dystrophin and Dystrophin-Associated Proteins in mdx Mice

et al. 2007

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Previously published online as a Cell Cycle E-publication: http://www.landesbioscience.com/journals/cc/abstract.php?id=4182 KEy wordS ABStrACtDuchenne Muscular Dystrophy (DMD) is an incurable inherited disease of childhood, characterized by progressive muscle degeneration and weakness. Our previous findings supported the idea that dystrophin and associated proteins, absent or greatly reduced in DMD, are degraded in dystrophin-deficient muscle by the proteasomal-dependent pathway. Indeed, treatment with the proteasome inhibitor MG-132 of skeletal muscles from mdx mice -a spontaneous mouse model of DMD-as well as from DMD patients, effectively rescued the expression and correct cellular localization of dystrophin and associated proteins. These promising results led us to further explore the use of proteasome inhibitors as a therapy for DMD. Therefore, we directed our attention towards two new dipeptide boronic acid inhibitors blocking the proteasomal-dependent degradation pathway: Velcade (bortezomib or PS-341) and MLN273 (PS-273). The exciting aspect of this development is that these drugs have already progressed to preclinical and clinical trials, in different fields than muscular dystrophy. Indeed, Velcade has been already FDA-approved for treatment of multiple myeloma and its side effects had been already explored and managed. Promisingly, MLN273 is currently in the preclinical trial phase. Here, we test the effectiveness of Velcade and MLN273 by local injection into the gastrocnemius muscle of mdx mice. We show the rescue of expression and membrane localization of a-dystroglycan, b-dystroglycan, a-sarcoglycan, and dystrophin after Velcade and MLN273 localized treatment, versus untreated (PBS only) mdx mice. Intriguingly, we also show that localized treatment with Velcade and MLN273 reduces the activation of Nuclear Factor-kappaB (NFkB). Because the NFkB pathway has been shown to be involved in inflammation responses in myopathies and DMD, our current results may have important clinical implications. Clearly, more investigations are needed, but our results emphasize the effectiveness of the pharmacological approach as a potential treatment for Duchenne muscular dystrophy.

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Section: Discussionmentioning

confidence: 99%

Localized Treatment with a Novel FDA-Approved Proteasome Inhibitor Blocks the Degradation of Dystrophin and Dystrophin-Associated Proteins in mdx Mice

et al. 2007

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“…This induction of CD11a, CD49d and CD54 expression on MM.1S cells occurred in a timedependent fashion (Table 2). Culture with proteasome inhibitor PS-341 (Palombella et al, 1998) blocked TNFa-induced upregulation of CD54 (ICAM-1) expression on RPMI-8226 cells (Figure 4), as well as on MM.1S cells (data not shown).…”

Section: Tnfa Induces Adhesion Molecules On MM Cell Linesmentioning

confidence: 99%

“…Since there is a TNFa response element in the IL-6 promoter (Ray et al, 1989), the indirect e ects of TNFa mediated via IL-6 are also of great interest. Finally, TNFa is known to induce NF-kB-dependent expression of adhesion molecules (Palombella et al, 1998;Li et al, 2000), further supporting its potential role in altering binding of MM cells to BMSCs within the BM millieu.…”

Section: Introductionmentioning

confidence: 99%

The role of tumor necrosis factor α in the pathophysiology of human multiple myeloma: therapeutic applications

et al. 2001

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“…Specifically bortezomib, a boronic acid dipeptide with selective activity as a proteasome inhibitor, has been shown to inhibit NF-kB activity in malignant cells [20,23]. Inhibitors of the proteasome decrease NF-kB activation and have anti-inflammatory activity in vivo [24,25]. So far the role of the proteasome and its inhibition has not been analyzed in greater detail in EAE and MS.…”

Section: Introductionmentioning

confidence: 99%

Dual inhibition of proteasomal and lysosomal proteolysis ameliorates autoimmune central nervous system inflammation

et al. 2008

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Multiple sclerosis (MS) is a detrimental disease of the central nervous system (CNS) leading to long-term disability. In the course of animal models of multiple sclerosis (experimental autoimmune encephalomyelitis), we find enhanced activity of proteasome subunits b1i, b2, b2i and b5 in the CNS. We demonstrate that pharmacological inhibition of the proteasome by bortezomib ameliorates experimental autoimmune encephalomyelitis in mice and rats in prophylactic and therapeutic treatment with reduced numbers of T-cells secreting proinflammatory cytokines. The anti-inflammatory effect of proteasome inhibition was accompanied by reduced NF-jB activity in the CNS and lymphoid organs. The combined inhibition of proteasomes and lysosomal proteases involved in major histocompatibility complex II antigen presentation further improved therapeutic efficacy. We suggest proteasome inhibition alone or in combination with inhibition of lysosomal proteases as a novel therapeutic strategy against inflammation-induced neurodegeneration in the CNS. We demonstrate the impact of the proteasome and lysosomal proteases on development of autoimmunity.

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Role of the proteasome and NF-κB in streptococcal cell wall-induced polyarthritis

Cited by 273 publications

References 46 publications

Localized Treatment with a Novel FDA-Approved Proteasome Inhibitor Blocks the Degradation of Dystrophin and Dystrophin-Associated Proteins in mdx Mice

Localized Treatment with a Novel FDA-Approved Proteasome Inhibitor Blocks the Degradation of Dystrophin and Dystrophin-Associated Proteins in mdx Mice

The role of tumor necrosis factor α in the pathophysiology of human multiple myeloma: therapeutic applications

Dual inhibition of proteasomal and lysosomal proteolysis ameliorates autoimmune central nervous system inflammation

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