pr-957 and Inflammation

Low molecular mass polypeptide 7 (LMP7) is an immunoproteasome subunit that regulates T cell amplification, differentiation, and inflammation and is involved in rheumatoid arthritis (RA) progression. This study intended to apply PR-957 (an anti-LMP7 agent) for RA treatment in vitro and in vivo and evaluate its interaction with LMP7-mediated CD4. PR-957 ameliorates RA progression and inflammation by repressing LMP7-mediated CD4

Topics: Animals; Arthritis, Experimental; Arthritis, Rheumatoid; CD4-Positive T-Lymphocytes; Humans; Inflammation; Leukocytes, Mononuclear; Mice; Peptides; T-Lymphocytes, Regulatory; Th1 Cells; Th17 Cells

Topics: Animals; Anti-Inflammatory Agents; Cells, Cultured; Coxsackievirus Infections; Disease Models, Animal; Enterovirus B, Human; Host-Pathogen Interactions; Inflammation; Male; Mice, Knockout; Myeloid Cells; Myocarditis; Myocytes, Cardiac; Oligopeptides; Proteasome Endopeptidase Complex; Proteasome Inhibitors; Proteolysis

Low-molecular mass protein 7 (LMP7) is a proteolytic subunit of the immunoproteasome that is involved in regulating inflammatory responses. However, the role of LMP7 in the pathogenesis of abdominal aortic aneurysm (AAA) remains unknown. In this study, ApoE knockout (KO) or LMP7/ApoE double KO (dKO) mice were infused with angiotensin II (Ang II, 1000 ng/kg per minute) for up to 28 d. We found that LMP7 expression was significantly upregulated in AAA tissues from ApoE KO mice and human patients. Moreover, Ang II infusion markedly increased the incidence and severity of AAA in ApoE KO mice, which was considerably reduced in LMP7/ApoE dKO mice. Histological alterations, including aortic wall thickening, collagen deposition, elastin fragmentation, and vascular smooth muscle cell apoptosis in AAA tissue of ApoE KO mice, were also significantly attenuated in LMP7/ApoE dKO mice. Interestingly, LMP7/ApoE dKO mice showed a marked reduction of infiltration of CD3

Topics: Animals; Aortic Aneurysm, Abdominal; Biocatalysis; Inflammation; Mice; Mice, Inbred C57BL; Mice, Knockout; Oligopeptides; Proteasome Endopeptidase Complex; Proteasome Inhibitors; Th1 Cells; Th17 Cells

There are currently no effective treatments to prevent spontaneous preterm labor. The precise upstream biochemical pathways that regulate the transition between uterine quiescence during pregnancy and contractility during labor remain unclear. It is well known however that intrauterine inflammation, including infection, is commonly associated with preterm labor. In this study, we identified the immunoproteasome subunit low-molecular-mass protein (LMP)7 mRNA expression to be significantly upregulated in laboring human myometrium. Silencing LMP7 using siRNA-targeted knockdown of LMP7 and its inhibitor ONX-0914 in human myometrial cells and tissues decreased proinflammatory cytokines (IL-6), cell chemotaxis (CXCL8, CCL2 expression, and THP-1 migration), cell to cell adhesion (ICAM1 expression and myometrial adhesion), contraction-associated proteins (PTGS2, FP, PGE2, and PGF2α), as well as suppressing contractions in myometrial cells and in myometrial tissues obtained from laboring women. In addition, LMP7 silencing reduced NF-κB RelA activity. ONX-0914 alleviated inflammation (CCL3, CXCL1, PTGS2, and IL-6) in myometrium, placenta, fetal brain, amniotic fluid, and maternal serum induced by LPS in pregnant mice. Collectively, our data suggest a novel role for ONX-014 to suppress uterine activation and contractility associated with preterm labor.

Topics: Animals; Cell Adhesion; Cell Line, Tumor; Chemokine CCL2; Female; Humans; Inflammation; Interleukin-6; Interleukin-8; Lipopolysaccharides; Mice; Mice, Inbred C57BL; Models, Animal; Myometrium; Obstetric Labor, Premature; Oligopeptides; Pregnancy; Proteasome Endopeptidase Complex; Proteasome Inhibitors; RNA Interference; RNA, Small Interfering; THP-1 Cells; Transcription Factor RelA; Uterine Contraction

Multiple sclerosis (MS) is a chronic demyelinating immune mediated disease of the central nervous system. The immunoproteasome is a distinct class of proteasomes found predominantly in monocytes and lymphocytes. Recently, we demonstrated a novel function of immunoproteasomes in cytokine production and T cell differentiation. In this study, we investigated the therapeutic efficacy of an inhibitor of the immunoproteasome (ONX 0914) in two different mouse models of MS. ONX 0914 attenuated disease progression after active and passive induction of experimental autoimmune encephalomyelitis (EAE), both in MOG₃₅-₅₅ and PLP₁₃₉₋₁₅₁-induced EAE. Isolation of lymphocytes from the brain or spinal cord revealed a strong reduction of cytokine-producing CD4(+) cells in ONX 0914 treated mice. Additionally, ONX 0914 treatment prevented disease exacerbation in a relapsing-remitting model. An analysis of draining lymph nodes after induction of EAE revealed that the differentiation to Th17 or Th1 cells was strongly impaired in ONX 0914 treated mice. These results implicate the immunoproteasome in the development of EAE and suggest that immunoproteasome inhibitors are promising drugs for the treatment of MS.

Topics: Animals; Brain; Cell Differentiation; Disease Models, Animal; Disease Progression; Encephalomyelitis, Autoimmune, Experimental; Female; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Inflammation; Mice; Mice, Inbred C57BL; Myelin-Oligodendrocyte Glycoprotein; Oligopeptides; Peptide Fragments; Proteasome Endopeptidase Complex; Proteasome Inhibitors; Spinal Cord; T-Lymphocytes