Production Of Multiple Pro-inflammatory Cytokines Research Articles

Poly-T oligonucleotides enhance TLR7/8 agonist induced responses in glial cells through a TLR7-dependent mechanism (135.11)

Abstract The brain does not contain a resident dendritic cell population so resident cells such as microglia and astrocytes play an important role in initiating innate immune responses in the central nervous system (CNS) following virus infection. However, the activation of these cells following stimulation of virus-recognizing toll-like receptors (TLRs) such as TLR7 and TLR8 remains unclear. Poly T oligonucleotides (pT-ODNs) were recently shown to enhance signaling through TLR8, including murine TLR8 which was previously thought to be non-functional. In the current study, we analyzed the ability of pT-ODNs to enhance TLR7/8 activation of murine astrocytes and microglia. We found that the TLR7/8 agonist CL075 (3M002) induced the expression of glial cell activation markers and induced the production of multiple proinflammatory cytokines and chemokines. Addition of pT-ODNs enhanced the expression of proinflammatory cytokines and chemokines as well as the microglia/macrophage activation markers F4/80 and Iba1. Surprisingly, pT-ODNs enhancement of CL075-induced glial activation was abolished in TLR7 deficient mice, with the exception of Gfap (glial fibrillary acidic protein) mRNA upregulation. Thus in glial cells, pT-ODNs enhanced TLR7/8-induced proinflammatory responses through a TLR7-dependent pathway. This research was supported by the Intramural Research Program of the NIH.

Mycophenolate mofetil and animal models

Mycophenolate mofetil (MMF), is the morpholinoethyl ester of mycophenolic acid (MPA). Though initially developed as an anti-rejection treatment, MMF is beginning to find application in more common immune-mediated diseases. MMF has been shown to be effective against transplant-associated vascular disease, lupus and other inflammatory diseases via multiple mechanisms in several animal models. MMF treatment blocks the proliferation of T cells and B cells, attenuates the production of autoreactive IgG and IgM, diminishes complement deposition, and reduces the production of multiple proinflammatory cytokines including TNF-α, IFN-γ, IL-2, IL-3, IL-4, IL-5, IL-6 and IL-12. It also increases production of the anti-inflammatory mediator IL-10. In addition, MMF reduces the infiltration of immune cells into sites of inflammation by interfering with the expression of cell-surface molecules critical for this process, including MHC class II, CD40, CD80, CD86, I-A, and ICAM-1. Additional mechanisms involving mannosylation and N-linked glycosylation of cell-surface molecules are only beginning to be investigated. This article will focus on the contribution of animal models of disease as investigational tools in the development of MMF as an immunomodulatory drug. The use of mice, rats, rabbits, monkeys, baboons and interspecific xenografts will be discussed.

Interleukin 10 treatment for rheumatoid arthritis

Interleukin (IL) 10 looms as a highly promising treatment for rheumatoid arthritis (RA) because of its capacity to inhibit cellular immunity and deactivate macrophages. In RA, activated CD4 T helper...