Signal cascades in monocyte activation

Cytokines are key mediators for the development and homeostasis of hematopoietic cells, critical for host defense, but also for the development of autoimmune and inflammatory disease such as inflammatory bowel disease (IBD), psoriasis, rheumatoid arthritis (RA), or juvenile idiopathic arthritis (JIA). Blocking cytokine action by interfering with the ligand-receptor association has been successfully employed to treat several immune disorders. While biologics typically target selectively only one single cytokine, the emergence of inhibitors that inhibit a subgroup of cytokines could be useful. Several cytokines (e.g. IL-2, IL-6, IFNg, GM-CSF) signal through Janus kinases (JAKs), a family of cytoplasmic protein tyrosine kinases currently comprising 4 members (JAK1,2,3, and Tky2). Thus, JAK inhibitors may help patients not responding to previous therapies. However, the disadvantage is the ubiquitous expression of JAKs and thus systemic treatment might lead to severe impairment of cellular networks. JAKs, however, have recently gained significant attention as therapeutic targets in inflammation and autoimmunity, and several JAK inhibitory small molecules have been developed. Efficacy and safety data suggest that some of these oral JAK inhibitors as well as their topical formulations may soon enter the daily clinical practice e.g. in psoriasis, lupus erythematodes or other inflammatory diseases. 

Monocytes play a key role in bridging natural and acquired immunity providing immediate defence against pathogens and assist during the development of the adaptive immune response. Monocytes differentiate into macrophages and dendritic cells (DCs) and are crucial for nearly every step of an immune reaction, including the control of both progression and resolution of inflammation. There is only little information about effects of blocking JAKs in cells of the innate immune arm (e.g. monocytes) especially in the context of a milieu that is prone to inflammation by multiple signals. Elucidation of the mode of action of JAK family members will lead to a better understanding and treatment of auto-inflammatory as well as autoimmune diseases.

 
 
 
 

Project Responsibles: 

Georg Varga, PhD

Anna Friederike Cordes, MD