Cytokine Signalling Pathways of JAK Kinases

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1		Przemysław Kotyla	--	1274	2022-08-16 10:57:54	\|
2	format correct	Conner Chen	Meta information modification	1274	2022-08-18 02:20:34	\|

This entry is adapted from the peer-reviewed paper 10.3390/ph15080936

The discovery of JAK kinases, which are tyrosine kinases coupled with cytokine receptors, may open a new chapter in the treatment of so far untreatable diseases.

systemic lupus erythematosus systemic sclerosis JAK inhibitors cytokine network

1. Introduction

Connective tissue diseases are a group of chronic diseases with an autoimmune background. Recent advances in genetics, pathology, and clinical immunology have started to explain the potential mechanisms responsible for the initiation and propagation of these diseases ^[1]^[2]. Unfortunately, with a few exceptions, this progress has not translated to the development of new disease-specific drugs that can interact with these key immunological disease-critical mechanisms. In fact, the result of treatment is still based on non-specific immunosuppression realized mainly via steroid and cytotoxic drug administration ^[3]^[4]. The result of this immunosuppression is the reduction of the central and peripheral activity of the dysregulated immune system. Among the many not fully elucidated mechanisms leading to the restoration of the proper function of the immune system, cytokine activity is believed to play an important role ^[5]. Cytokines are soluble intercellular crosstalk transmitters, which are responsible for modulating immune system functioning. However, in the setting of immune dysregulation, cytokines become the executive arm of autoimmunity directly responsible for maintaining the autoimmune response. This is especially true for inflammatory arthropathies, where the role of some proinflammatory cytokines is well established. At the end of the last century, the understanding of the role of some proinflammatory cytokines, e.g., TNFα, IL-1, IL-6, or IL-17, translated to the development of high-affinity molecular antibodies blocking these cytokines’ function and halting disease progression.

At that time, almost all the scientific papers on rheumatoid arthritis started with the sentence “TNF is a key cytokine in RA development”, suggesting that people had finally found the ‘holy grail’ and that people would be able to successfully treat all inflammatory conditions ^[6]^[7]^[8]. With the progression of research, it became clear that blocking only one cytokine is not enough to stop an autoimmune response and that the plethora of cytokines, chemokines, and intercellular signals cannot be stopped with only one drug. Moreover, despite several similarities in the clinical pictures, rheumatic conditions differ between each other in terms of their pathophysiological background and mechanisms of inflammatory response. Therefore, one effective drug in a given rheumatic disease does not work in all others and vice versa. That was the strong impulse for the identification of disease specific mediators and the invention of the drugs capable of inhibiting them. Indeed, the progress in understanding the pathophysiological background of some rheumatic diseases translated to the development of anti-cytokine drugs that proved to be efficacious in the treatment of many (but not all) aspects of inflammation. These drugs, commonly referred to as biological disease modifying drugs (bDMARDs) or more commonly as biologics, revolutionized the treatment of inflammatory arthritides. The mode of action of biologics is based mainly on blocking the inflammatory cytokines; however, other mechanisms have been successfully used, such as depleting the population of antibody producing B-cells and interfering in the co-stimulation of immunocompetent cells. Unfortunately, blocking one cytokine with specific biologics is sometimes clinically infective; in addition, the treatments can lose their efficacy over time due to immunogenicity or the activation of the other signalling pathways, thereby bypassing the cytokine already blocked.

Despite the therapeutic efficacy of biological DMARDs, it has become evident that treatment with bDMARDs has several limitations; thus, not all patients may benefit from such a treatment. Moreover, biologics are large proteins that are difficult to synthetize, and the parenteral route of administration is often an obstacle for patients. Treatment with biologics can produce adverse drug reactions such as tuberculosis, heart failure, neuropathies, and others ^[9]^[10]^[11].

In the early 1990s, the discovery of a family of intracellular tyrosine kinases attached to several cytokine receptors resulted in the further discovery of the pathway that transmits signals from a cytokine to the nucleus. The fact that the role of this discovery was not completely understood explains the term initially used to characterize them—“just another kinase”.

The discovery of the immune pathway that orchestrates the immune mechanism translated to the quest for new therapeutic approaches. Among several mechanisms that transmit cytokine signals to the nucleus, the JAK/STAT pathway is of special interest, as it is responsible for transmitting signals from many cytokines within the same signaling pathway.

Recently, a new class of low-weight compounds capable of blocking several cytokines was developed and tested in chronic conditions including rheumatoid arthritis, psoriatic arthritis, and haematological diseases. These drugs are commonly referred to as JAK kinase inhibitors or (Jakinibs). To understand the role of these specific cytokines people must be aware that these low molecular weight proteins or glycoproteins may orchestrate not only the peripheral immune system but also act in the central phase of the immune response when antigen or autoantigen recognition takes place. During the recognition of an antigen presented by antigen presenting cells to a naïve T cell, a plethora of cytokines acting as co-stimulatory signals is released. Moreover, the activated immunocompetent cells can synthesize and release other cytokines that regulate the survival, development, and function of other immune and non-immune cells. Cytokines signal via a wide variety of receptor structures categorized into several receptor superfamilies. After their interaction with the extracellular domain of the receptor, they can activate long chains of transmission molecules to activate specific genes in the nucleus.

2. Cytokine Signalling Pathways

The essential role in transmitting cytokine signals is played by protein kinases attached to the intracellular part of the receptors. Cytokine signalling and the regulation of their activity is realized via the interaction between cytokines, chemokines, and growth factors commonly referred to as ligands and the extracellular domain of the given receptor. Several types of receptors are involved in this process and are usually categorized into receptor subfamilies. Among them people may distinguish the TNF receptor subfamily, the IL-1 subfamily receptors, and the IL-17 and Janus kinase-associated receptors. The TNF receptor subfamily signal via TNFR and transmit their signal by further utilizing transmission molecules such as TRADD, TRAF2, and RIP1, resulting in the activation of NF-κB and MAPK signalling and the subsequent gene activation and expression of pro-inflammatory cytokines, such as interleukin 6 and 8 (IL-6 and IL-8) ^[12]^[13]. IL-1 subfamily receptors transmit signals from the IL-1 family (IL-1, IL-33, and IL-36) to the nucleus through the use of MyD88 and IRAK adaptor proteins ^[14]^[15]. The other important proinflammatory signals are transmitted via IL-17. Upon interaction with its receptors, IL-17 activates multiple signalling cascades resulting in the activation of the NF-κB, C/EBPβ, C/EBPδ, and MAPK pathways ^[16]. However, considering the number of cytokine signals that are transmitted, the Janus kinases associated with cytokine specific receptors play an important role by interacting with more than 50 cytokines belonging to the class I and class II superfamily cytokines ^[17].

As the JAK kinases can be easily blocked with small synthetic compounds, JAK kinases are a promising target to halt cytokine signalling and restore immune balance. This hypothesis was successfully tested, and several JAK inhibitors were introduced to common clinical practices demonstrating their safety and efficacy in the treatment of several hematologic conditions and inflammatory arthropathies (rheumatoid arthritis, psoriatic arthritis, and spondyloarthropathies) ^[18]. Taking into account the many similarities between inflammatory arthropathies and connective tissue diseases, it would be reasonable to establish whether there is a role for JAK kinase inhibitors in the treatment of connective tissue diseases (CTDs) ^[19]^[20]. This finding may be especially important considering the lack of accepted therapies for treating connective tissue diseases. Since inflammation, orchestrated by a network of pro- and anti-inflammatory cytokines, plays an unequivocal role in the development of several CTDs, new therapeutic strategies targeting the inflammatory and signalling pathways may offer promising opportunities.

References

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Subjects: Rheumatology

Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :

Przemysław Kotyla

Olga Gumkowska-Sroka

Bartosz Wnuk

Kacper Kotyla

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Update Date: 18 Aug 2022

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1. Introduction

2. Cytokine Signalling Pathways

References