Anti-Inflammatory and Immunomodulatory Effects of Bortezomib in Various in vivo Models

Tung, David; Cheung, Peter H.; Kaur, Pali; Foreman, Oded; Kavirayani, Anoop; Hain, Heather S.; Saha, Saurabh

doi:10.1159/000330067

Cited by 18 publications

(19 citation statements)

References 95 publications

(45 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Keratinocytes at the site of CD overexpress numerous cytokines and chemokines, such as TNF-α, IFN-γ, MCP-1 and IL-10 (17-19). It has been previously reported that IFN-γ is important in the development of skin hypertrophy, and TNF-α and MCP-1 function as stimulants of immune cell recruitment around blood vessels (17)(18)(19). In the present study, the topical application of MEKS inhibited the histopathological features of CD via suppression of TNF-α, IFN-γ and MCP-1 expression.…”

supporting

confidence: 59%

Anti-inflammatory activity of Kochia scoparia fruit on contact dermatitis in mice

Ryu

Han

et al. 2015

Molecular Medicine Reports

View full text Add to dashboard Cite

Abstract. The mature fruit of Kochia scoparia (L.) Schrad. is widely administered in China and Korea as a medicinal herb for treatment of skin diseases, diabetes mellitus and rheumatoid arthritis. The present study investigated the effects of methanol extracts of K. scoparia dried fruit (MEKS) on ear swelling, histopathological changes (such as epidermal acanthosis, spongiosis and immune cell infiltration) and cytokine production in 1-fluoro-2,4-dinitrofluorobenzene (DNFB)-induced contact dermatitis mice. Topical application of MEKS inhibited DNFB-induced ear thickness and weight increases, as well as DNFB-induced epidermal acanthosis, spongiosis and immune cell infiltration. In addition, treatment with MEKS significantly decreased the levels of tumor necrosis factor-α, interferon-γ and monocyte chemotactic protein-1 in inflamed tissues. These data indicate that the mature fruit of K. scoparia has the potential to be administered for the treatment of inflammatory skin diseases and that the anti-inflammatory action of K. scoparia is involved in the inhibition of type 1 T helper cell skewing reactions.

show abstract

supporting

confidence: 59%

Anti-inflammatory activity of Kochia scoparia fruit on contact dermatitis in mice

Ryu

Han

et al. 2015

Molecular Medicine Reports

View full text Add to dashboard Cite

show abstract

“…The identification of the skin as a significant target of Bz is well compatible with the literature. For example, a recent report demonstrated that the topical application of Bz to the skin caused erythema and skin thickening (characteristics of AD) in a murine model of psoriasis . Likewise, proteasome integrity is essentially implicated in preventing misfolded keratins from aggregation, especially in keratin genodermatoses , is important for the regulation of p53 levels in keratinocytes and for the maintenance of keratinocyte contacts through stabilization of desmosomes .…”

Section: Discussionmentioning

confidence: 99%

Opposing effects on immune function and skin barrier regulation by the proteasome inhibitor bortezomib in an allergen‐induced eczema model

Mudnakudu-Nagaraju

Babina

Worm

2013

Experimental Dermatology

View full text Add to dashboard Cite

Proteasome inhibition (PI) has been reported to interfere with antibody-driven autoimmune diseases. The impact of PI on the allergic immune response and on skin diseases like atopic dermatitis (AD) has not been thoroughly explored, however. Here, we examined whether the PI bortezomib interferes with the allergic immune response and the severity of AD by using an established mouse model of allergen-driven dermatitis, to which bortezomib was applied after the establishment of systemic sensitization to ovalbumin. The treatment indeed resulted in a remarkable decrease in total and allergen-specific plasma cells/antibody-secreting cells, as evidenced by flow cytometry and ELISpot, respectively. This was accompanied by rapid reductions in serum antibody titres, including a prominent reduction of the IgE isotype. CD4+ and CD8+ cells were greatly diminished in lesional skin on immunohistological staining. The impressive effects at the level of immune modulation did not result in any improvement in the eczema, however. Following up on this unexpected result, we found that the skin itself was susceptible to bortezomib, by which it was instructed to lower the expression of critical skin barrier genes, especially transglutaminase-1 and filaggrin. Together, bortezomib eliminates plasma cells and decreases immunoglobulin responses, including allergenic IgE. Although anti-inflammatory effects are detectable in the skin, counter-regulatory effects from PI on resident skin cells likely undermine improvement in the eczema. These results caution against the therapeutic use of bortezomib for inflammatory skin disorders, which are characterized by inherently impaired barrier function, especially AD.

show abstract

“…Perfusion rates taken by the PSI System were measured as perfusion units (PU) and calculated by the software PIMsoft (Perimed). Bortezomib (0.005 mg/kg/d) was transdermally administered (20 μl, 1 X/d and 24 h before surgery) in a formulation containing 70.8% propylene glycol, 28.2% water, and 1.0% HPC (w/v), as described by Tung et al (20). After 4 or 7 d on ligation, mice were euthanized and perfused with Ringer solution and zinc fixative.…”

Section: Methodsmentioning

confidence: 99%

Bortezomib protects from varicose‐like venous remodeling

et al. 2014

View full text Add to dashboard Cite

Despite the high prevalence of venous diseases that are associated with and based on the structural reorganization of the venous vessel wall, not much is known about their mechanistic causes. In this context, we demonstrated that the quantity of myocardin, a transcriptional regulator of the contractile and quiescent smooth muscle cell phenotype, was diminished in proliferating synthetic venous smooth muscle cells (VSMCs) of human and mouse varicose veins by 51 and 60%, respectively. On the basis of the relevance of proteasomal activity for such phenotypic changes, we hypothesized that the observed VSMC activation is attenuated by the proteasome inhibitor bortezomib. This drug fully abolished VSMC proliferation and loss of myocardin in perfused mouse veins and blocked VSMC invasion in collagen gels by almost 80%. In line with this, topical transdermal treatment with bortezomib diminished VSMC proliferation by 80%, rescued 90% of VSMC myocardin abundance, and inhibited varicose-like venous remodeling by 67 to 72% in a mouse model. Collectively, our data indicate that the proteasome plays a pivotal role in VSMC phenotype changes during venous remodeling processes. Its inhibition protects from varicose-like vein remodeling in mice and may thus serve as a putative therapeutic strategy to treat human varicose veins.

show abstract

Anti-Inflammatory and Immunomodulatory Effects of Bortezomib in Various in vivo Models

Cited by 18 publications

References 95 publications

Anti-inflammatory activity of Kochia scoparia fruit on contact dermatitis in mice

Anti-inflammatory activity of Kochia scoparia fruit on contact dermatitis in mice

Opposing effects on immune function and skin barrier regulation by the proteasome inhibitor bortezomib in an allergen‐induced eczema model

Bortezomib protects from varicose‐like venous remodeling

Contact Info

Product

Resources

About