Title: Dysfunctional Immune-Mediated Inflammation in Rheumatoid Arthritis Dictates that Development of Anti-Rheumatic Disease Drugs Target Multiple Intracellular Signaling Pathways
Volume: 10
Issue: 2
Author(s): Charles J. Malemud
Affiliation:
Keywords:
Autoimmunity, drug development, inflammation, JAK/STAT, PI3K/AKT, SAP/MAPK, rheumatoid arthritis, phosphatidylinosotide, kinase, synovial fluid
Abstract: A skewed repertoire of pro-inflammatory cytokines produced by the Th1 subset, one of the hallmarks of rheumatoid arthritis (RA), is characterized by an overabundance of pro-inflammatory cytokines. Tumor necrosis factor-α, interleukin- 1 (IL-1), IL-6, IL-7, IL-8, IL-21, IL-12/IL-23, IL-15, IL-17, IL-18, IL-32, and interferon-γ are primarily responsible for immune-mediated inflammation of RA by activating Janus kinases (JAK) -1, -2, -3, p38 kinase, C-Jun-Nterminal kinase, extracellular signal-regulated kinase 1/2 and the phosphatidylinosotide-3-kinase/Akt/mTor pathways. Activation of these signaling pathways results in up-regulation of pro-inflammatory cytokines, cyclooxygenase-2, matrix metalloproteinases, pro-angiogenesis proteins and anti-apoptosis proteins, the latter resulting in abnormal survival of activated T- and B-cells. Further, IL-17 also regulates the differentiation of CD4+ T-helper cells by inducing a Th17 T-cell subset, and a subpopulation of T-regulatory (Treg) cells. Although Treg cells are sufficiently abundant in RA synovial fluid, they fail to induce immune tolerance suggesting a functional deficiency likely coupled to putative protein kinase signaling abnormalities. The results of in vitro and studies in animal models of arthritis have indicated that inhibiting individual signaling pathways can blunt the synthesis of several of the pro-inflammatory biomarkers characteristic of human RA pathology. However, RA clinical trials indicated that small molecule inhibitors of JAK-1, -2-, 3 and/or p38 kinase while exhibiting acceptable safety and tolerability profiles have only marginal and transient clinical effectiveness. These results suggested that future RA clinical studies using these or other kinase inhibitors will have to consider strategies designed to simultaneously inhibit multiple kinase pathways.
