Small molecules to the rescue: Inhibition of cytokine signaling in immune-mediated diseases

Abstract

Cytokines are small, secreted proteins associated with the maintenance of immune homeostasis but also implicated with the pathogenesis of several autoimmune and inflammatory diseases. Biologic agents blocking cytokines or their receptors have revolutionized the treatment of such pathologies. Nonetheless, some patients fail to respond to these drugs or do not achieve complete remission. The signal transduction originating from membrane-bound cytokine receptors is an intricate network of events that lead to gene expression and ultimately regulate cellular functionality. Our understanding of the intracellular actions that molecules such as interleukins, interferons (IFNs) and tumor necrosis factor (TNF) set into motion has greatly increased in the past few years, making it possible to interfere with cytokines' signaling cascades. The Janus kinase (JAK)/signal transducer and activator of transcription (STAT), the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB), the mitogen activated protein kinase (MAPK) and the Phosphatidylinositol-3'-kinases (PI3K) pathways have all been intensively studied and key steps as well as molecules have been identified. These research efforts have led to the development of a new generation of small molecule inhibitors. Drugs capable of blocking JAK enzymatic activity or interfering with the proteasome-mediated degradation of intermediates in the NF-kB pathway have already entered the clinical arena confirming the validity of this approach. In this review, we have recapitulated the biochemical events downstream of cytokine receptors and discussed some of the drugs which have already been successfully utilized in the clinic. Moreover, we have highlighted some of the new molecules that are currently being developed for the treatment of immune-mediated pathologies and malignancies.

Keywords: Autoimmunity; Cytokines; Drug development; Inflammation; Signal transduction; Therapy.

Figure 1

Type 1 and type 2 cytokines signaling cascade is dependent on the enzymatic activity of members of the Janus kinase family: JAK1, JAK2, JAK3 and TYK2. These enzymes phosphorylate STATs. First-generation JAK inhibitors (red line) block more than one JAK and consequently, inhibit the effect of several cytokines. Selective JAK inhibitors (green line: JAK1; purple line: JAK3, blue line: TYK2), instead have the potential to limit the activity of only selected cytokines.

Figure 2

Schematic representation of signaling pathways that are activated by IL-1, IL-17, and TNF. The major pathways activated by these cytokines are the NF-kB, MAPK and the GSK3β–C/EBPδ/β pathways, ultimately leading to the regulation of gene expression.

Figure 3

PI3K is rapidly activated upon the engagement of different cytokine receptors. AKT is a PI3K substrate which, in turn, activates the mTOR complexes thereby regulating numerous cellular functions such as metabolism, protein synthesis, cell growth, proliferation, and survival as well as cytoskeletal rearrangement.