The Small Tellurium Compound AS101 Ameliorates Rat Crescentic Glomerulonephritis: Association with Inhibition of Macrophage Caspase-1 Activity via Very Late Antigen-4 Inactivation

Abstract

Crescentic glomerulonephritis (CGN) is the most aggressive form of GN and, if untreated, patients can progress to end-stage renal failure within weeks of presentation. The α4β1 integrin very late antigen-4 (VLA-4) is an adhesion molecule of fundamental importance to the recruitment of leukocytes in inflammation. We addressed the role of VLA-4 in mediating progressive renal injury in a rat model of CGN using a small tellurium compound. AS101 [ammonium trichloro(dioxoethylene-o,o′)tellurate]. This compound has been previously shown to uniquely inhibit VLA-4 activity by redox inactivation of adjacent thiols in the exofacial domain of VLA-4. The study shows that administration of AS101 either before or after glomerular basement membrane anti-serum injection ameliorates crescent formation or preserves renal function. This was associated with profound inhibition of critical inflammatory mediators, accompanied by decreased glomerular infiltration of macrophages. Mechanistic studies demonstrated vla-4 inactivation on glomerular macrophages both in vitro and in vivo as well as inhibition of caspase-1 activity. Importantly, this cysteine protease activity modification was dependent on VLA-4 inactivation and was associated with the anti-inflammatory activity of AS101. We propose that inactivation of macrophage VLA-4 by AS101 in vivo results in a decrease of inflammatory cytokines and chemokines produced in the glomeruli of diseased rats, resulting in decreased further macrophage recruitment and decreased extracellular matrix expansion. Thus, AS101, which is currently in clinical trials for other indications, might be beneficial for treatment of CGN.

Tellurium Compounds Prevent and Reverse Type-1 Diabetes in NOD Mice by Modulating α4β7 Integrin Activity, IL-1β, and T Regulatory Cells

“…Figure 10B shows that both AS101 and SAS significantly inhibited pancreatic IL-1 protein levels at 20 weeks. Furthermore, caspase-1 activity, previously shown to be inhibited by AS101 (16, 25) resulting in decreased IL-1β, was also inhibited in this study in PAN LN by AS101 and SAS-treated mice (Figure 10C). Importantly, the pro-inflammatory cytokine IL-17, which is implicated as essential in the development of T1D (26), was also inhibited in treated mice (Figure 10D).…”

“…IL-1 is a pleiotropic cytokine, which attenuates CD4 + CD25 + FoxP3 + regulatory T cell function, and allows the CD4 + CD25 − autoreactive effector subset to escape from suppression (24). IL-1β has been previously shown to be inhibited by AS101 in various pre-clinical studies (14, 16, 25). Figure 10B shows that both AS101 and SAS significantly inhibited pancreatic IL-1 protein levels at 20 weeks.…”

“…The decrease in Il-1β suggests that AS101 and SAS prevent insulitis not only by inhibiting the activity of the α4β7 integrin but also possibly by indirectly inhibiting the expression MAdCAM-1 on pancreatic vasculature via inhibition of IL-1β. This cytokine has been previously shown to be inhibited by the tellurium compounds in various preclinical studies due to inhibition of caspase-1 activity (14, 16, 26). Interestingly, we have recently shown that modulation of caspase-1 activity is dependent on VLA-4 inactivation and is mediated through VLA-4 inactivation, and underlies the anti-inflammatory activity of AS101 (16).…”

“…This cytokine has been previously shown to be inhibited by the tellurium compounds in various preclinical studies due to inhibition of caspase-1 activity (14, 16, 26). Interestingly, we have recently shown that modulation of caspase-1 activity is dependent on VLA-4 inactivation and is mediated through VLA-4 inactivation, and underlies the anti-inflammatory activity of AS101 (16). In line with this, the present study shows a significant decrease in pancreatic caspase-1 activity.…”

Resuspendable Powders of Lyophilized Chalcogen Particles with Activity against Microorganisms

“…Organoselenium compounds, in particular ebselen and its derivatives, pose a similar attraction in the Life Sciences, especially in the context of antioxidants [ 2 , 3 ]. In contrast, organotellurium compounds have long remained marginalized in Biology, yet some of them, such as RT-01 and AS101, have also recently emerged from the chemical closet with some prominence [ 2 , 4 , 5 , 6 ]. Not surprisingly, the field of biologically active organochalcogens has stimulated considerable efforts in chemical synthesis and has produced volumes of more or less exotic molecules [ 7 , 8 ].…”