NF-κB Activation for Constitutive Expression of VCAM-1 and ICAM-1 on B Lymphocytes and Plasma Cells

247

167

The protective effect of pregnancy on putative Th1-mediated autoimmune diseases, such as multiple sclerosis and rheumatoid arthritis, is associated with a Th1 to Th2 immune shift during pregnancy. The hormone estriol increases during pregnancy and has been shown to ameliorate experimental autoimmune encephalomyelitis and collagen-induced arthritis. In addition, estrogens induce cytokine changes consistent with a Th1 to Th2 shift when administered in vitro to human immune cells and in vivo to mice. In a pilot trial, oral estriol treatment of relapsing remitting multiple sclerosis patients caused significant decreases in enhancing lesions on brain magnetic resonance imaging. Here, the immunomodulatory effects of oral estriol therapy were assessed. PBMCs collected longitudinally during the trial were stimulated with mitogens, recall Ags, and glatiramer acetate. Cytokine profiles of stimulated PBMCs were determined by intracellular cytokine staining (IL-5, IL-10, IL-12 p40, TNF-α, and IFN-γ) and cytometric bead array (IL-2, IL-4, IL-5, IL-10, TNF-α, and IFN-γ). Significantly increased levels of IL-5 and IL-10 and decreased TNF-α were observed in stimulated PBMC isolated during estriol treatment. These changes in cytokines correlated with reductions of enhancing lesions on magnetic resonance imaging in relapsing remitting multiple sclerosis. The increase in IL-5 was primarily due to an increase in CD4+ and CD8+ T cells, the increase in IL-10 was primarily due to an increase in CD64+ monocytes/macrophages with some effect in T cells, while the decrease in TNF-α was primarily due to a decrease in CD8+ T cells. Further study of oral estriol therapy is warranted in Th1-mediated autoimmune diseases with known improvement during pregnancy.

Section: Discussionmentioning

confidence: 69%

Immune Modulation in Multiple Sclerosis Patients Treated with the Pregnancy Hormone Estriol

Soldan¹,

Retuerto²,

Sicotte³

et al. 2003

247

167

“…After transfection, the cells were lysed at 44 h, and the lysates were assayed for luciferase activities using the Luciferase Assay System (Promega, Madison, WI) (19,20). Notably, the pCMV␤ vector (BD Clontech, Palo Alto, CA) was cotransfected so that the transfection efficiencies could be normalized with the ␤-galactosidase activities determined using a Luminescent ␤-Gal Detection Kit II (BD Clontech).…”

Section: Transfection and Luciferase Assaymentioning

confidence: 99%

Andrographolide Attenuates Inflammation by Inhibition of NF-κB Activation through Covalent Modification of Reduced Cysteine 62 of p50

Xia

et al. 2004

Self Cite

340

285

NF-κB is a central transcriptional factor and a pleiotropic regulator of many genes involved in immunological responses. During the screening of a plant extract library of traditional Chinese herbal medicines, we found that NF-κB activity was potently inhibited by andrographolide (Andro), an abundant component of the plant Andrographis that has been commonly used as a folk remedy for alleviation of inflammatory disorders in Asia for millennia. Mechanistically, it formed a covalent adduct with reduced cysteine (62) of p50, thus blocking the binding of NF-κB oligonucleotide to nuclear proteins. Andro suppressed the activation of NF-κB in stimulated endothelial cells, which reduced the expression of cell adhesion molecule E-selectin and prevented E-selectin-mediated leukocyte adhesion under flow. It also abrogated the cytokine- and endotoxin-induced peritoneal deposition of neutrophils, attenuated septic shock, and prevented allergic lung inflammation in vivo. Notably, it had no suppressive effect on IκBα degradation, p50 and p65 nuclear translocation, or cell growth rates. Our results thus reveal a unique pharmacological mechanism of Andro’s protective anti-inflammatory actions.

“…As it is known that activation of B cells (via the B cell receptor, CD40, or MHC class II) or the expression of costimulatory molecules can be regulated by NF-B signaling (25,28,41,42), we investigated whether the BIS20x3-mediated costimulatory signals were also under control of the NF-B pathway. Pathways that regulate NF-B-mediated gene transcription have been described to be involved in CD20 signaling (43).…”

Section: Discussionmentioning

confidence: 99%

The Role of B Cell-Mediated T Cell Costimulation in the Efficacy of the T Cell Retargeting Bispecific Antibody BIS20x3

Stel¹,

Kroesen²,

Jacobs³

et al. 2004

In this study, we investigated the role of the naturally occurring B cell-mediated T cell costimulation in the antitumor efficacy of the bispecific Ab BIS20x3. BIS20x3 has a dual specificity for both CD20 and CD3 and has previously been shown to effectively direct the lytic potential of cytolytic T cells toward malignant, CD20+ B cells. BIS20x3 instigated T cell-B cell interaction caused a dose-dependent activation of T cells that was 30 times stronger when compared with T cell activation induced by monovalent anti-CD3 Abs. The activation of T cells by BIS20x3 and B cells appeared functional and resulted in the rapid induction of high lytic potential in freshly isolated peripheral T cells. BIS20x3-mediated T cell-B cell interaction resulted in a significant up-regulation of ICAM-1 on B cells and the activation of T cells was found to be dependent on the interaction of ICAM-1 with LFA-1 and trans-activation by the NF-κB pathway. Also, the lytic potential of freshly isolated T cells activated via BIS20x3 appeared to be dependent on NF-κB signaling in the target B cells. Interestingly, the costimulatory signaling effects described in this study appeared specifically related to the targeting against CD20 because targeting against CD19, by a CD3xCD19-directed bispecific Ab, was significantly less effective in inducing T cell activation and T cell-mediated B cell lysis. Together these results demonstrate that the malignant B cells actively contribute to their own demise upon CD20-directed bispecific Ab-mediated T cell targeting.