Dysfunctional Immune-Mediated Inflammation in Rheumatoid Arthritis Dictates that Development of Anti-Rheumatic Disease Drugs Target Multiple Intracellular Signaling Pathways

Abstract

A skewed repertoire of pro-inflammatory cytokines produced by the T h 1 subset, one of the hallmarks of rheumatoid arthritis (RA), is characterized by an overabundance of pro-inflammatory cytokines. Tumor necrosis factor-, 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-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 T h 17 T-cell subset, and a subpopulation of T-regulatory (T reg ) cells. Although T reg 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.

Intracellular Signaling Pathways in Rheumatoid Arthritis

“…In light of this contention, we recently suggested that dysfunctional intracellular signaling involving protein kinase pathways other than JAK/STAT as well as “cross-talk” between JAK/STAT and the stress-activated protein kinase/mitogen-activated protein kinase (SAPK/ MAPK) and Phosphatidylinositide-3-Kinase/AKT/mammalian Target of Rapamycin (PI-3K/AKT/mTOR) pathways is likely be required to completely dampen immune-mediated Inflammation and cartilage destruction in RA [26-28]. Supporting this viewpoint are the results of an analysis involving the therapy of active RA with the anti-IL-6 receptor inhibitor, tocilizumab [29].…”

Monosodium Urate and Tumor Necrosis Factor-α Increase Apoptosis in Human Chondrocyte Cultures

“…Since we did not determine the extent to which MSU altered NO levels in the normal juvenile chondrocyte pellet cultures, it remains to be determined if the MSU-mediated increase in TUNEL-positive chondrocytes also involved NO. This may prove to be critical because NO is also a potent inducer of chondrocyte apoptosis [1,10,28]. …”

Apoptosis Resistance in Rheumatoid Arthritis Synovial Tissue

“…Maintenance of the appropriate levels and biological activity of circulating T-regulatory (T reg ) cells are required for maintaining immune tolerance [48]. In that regard, Xiao et al [49] showed that T reg cells recovered from RA patients exhibited an impaired capacity to limit the proliferation and cytokine production of autologous T-effector cells which appeared to be due to an intrinsic defect in RA T reg cells .…”