Introduction

Mechanism of Action

Activate Janus kinase & signal transducer & activator of transcription (JAK-STAT) pathways. Janus kinases (JAKs) are intracellular proteins that are present at the intracytoplasmic component of cytokine receptors. Upon attachment of cytokines to extracellular ligands, JAKs become activated to phosphorylate signal transducer & activator of transcription (STAT) proteins, which dimerize & then translocate into the nucleus to activate proinflammatory cytokine genes & induce the release of various proinflammatory cytokines.

JAK Sub-types

JAK1, JAK2, JAK3, & TYK2

Cytokines JAK Sub-types Function Clinical Relevance
IL-6, IL-11, IL-27, Leukemia inhibitory factor (LIF), granulocyte colony stimulating factor (G-CSF) JAK1, JAK2, TYK2
  • Naïve T-cell differentiation
  • T-cell homeostasis
  • Lipid metabolism
  • Granulopoiesis
  • Inflammation
  • IL-6 in dermatomyositis & graft versus host disease
  • Risk of hyperlipidemia
IL-4, IL-13, IL-10, Interferon (IFN) -α & -β JAK1, TYK2
  • Anti-viral
  • Anti-tumor
  • Inflammation
  • Risk of malignancy & viral infections
  • IL-4 & IL-13 in atopic dermatitis
  • IFN- α & β in dermatomyositis
Interferon (IFN)- γ, IL-20, IL-22, Thymic stromal lymphopoietin (TSLP) JAK1, JAK2
  • Anti-viral
  • Anti-mycobacterial
  • Inflammation
  • Risk of viral & tuberculous infections
  • IFN- γ in vitiligo, alopecia areata, erythema multiforme
IL-2/4, IL-7/9, IL-15, IL-21 JAK1, JAK3
  • Maturation lymphoid cells
  • Differentiation/homeostasis T-cells, NK-cells
  • B-cell switching
  • Inflammation
  • Risk of lymphopenia
  • IL-2 & IL-21 in graft versus host disease
  • IL-15 in alopecia areata & dermatomyositis
  • IL-4 in atopic dermatitis
IL-12/23 JAK2, TYK2
  • Innate immunity
  • Differentiation/proliferation of Th17 cells
  • Inflammation
  • IL-12/23 in psoriasis
    IL-3/5, granulocyte macrophage colony stimulating factor GM-CSF, growth hormone (GH), erythropoietin (EPO), prolactin, leptin JAK2
    • Erythropoiesis
    • Myelopoiesis
    • Megakaryocyte/platelet production
    • Growth
    • Mammary development
    • Anemia
    • IL-5 in hypereosinophilic syndrome