JAK Inhibitors - HSS Study Reveals How New Drugs Help Stop Inflammation

HSS Authors
Anna Yarilina MD, PhD
Kai Xu
Chunhin Chan
Lionel B. Ivashkiv MD

Promising new drugs called JAK inhibitors are currently being tested in clinical trials, showing solid ability to suppress the chronic inflammation of rheumatoid arthritis (RA).

JAK is short for Janus kinase. Kinases are enzymes that can act on and regulate other proteins, to control cellular processes. JAK inhibitor drugs block JAK enzymes from those kinds of actions in important cellular pathways involved in inflammation. However, it has not been completely understood exactly how JAK inhibitors suppress inflammation in RA. Now, a recent HSS study has identified specific molecular mechanisms potentially responsible for how JAK inhibitors work in this disease.

Associate Chief Scientific Officer and David H. Koch Chair in Arthritis and Tissue Degeneration Lionel B. Ivashkiv, MD, and his lab, studied two JAK inhibitors currently being used to treat RA in clinical trial testing. The drugs are known as tofacitinib (CP-690,550) and ruxolitinib (INCB018424).

Dr. Ivashkiv and his team found that the two JAK inhibitors are able to suppress activation of large cells in the immune system called macrophages. The study showed that the drugs disrupt the responses of macrophages to the potent pathogenic cytokine tumor necrosis factor (TNF). This results in diminished production of specific proteins that are necessary for macrophages to trigger an inflammatory response.

Preventing Cytokine Production

When activated by an immune system challenge, normally macrophages would respond by expressing inflammation-promoting proteins called cytokines and chemokines. The cytokines signal other cells to launch specific molecular processes needed to create an inflammatory response, and the chemokines recruit additional immune cells to perpetuate inflammation. TNF is one of the most important cytokines involved in signaling for inflammation.

The research team found that JAK inhibitors prevented the macrophages from responding appropriately to TNF, so TNF did not induce expression of inflammatory cytokines and chemokines, including IL-1, IL-6 and CXCL10. The drug CP-690,550 also significantly decreased expression of a key cytokine involved in inflammatory signaling called interleukin-6 (IL6) in joint macrophages from RA patients.

If JAK inhibitors prevent macrophages from being activated enough to produce sufficient cytokines in the first place, then the full cellular signaling that triggers inflammation would be prevented from happening. Without enough inflammatory messengers, there would be no clear inflammatory message.

Interfering With Cellular Activation

When activated macrophages need cytokines to trigger inflammation, like any necessary cell, the cytokines have to be synthesized (produced). The study identified several key proteins required for cytokine production that JAK inhibitors can suppress.

One necessary protein is called STAT1, which stands for “Signal Transducer and Activator of Transcription”. STAT1 is a transcription factor, a protein that, appropriately, helps transcribe genetic information from DNA inside a cell’s nucleus, allowing the cell to express its genes.

STAT1 responds to immune system needs. JAK inhibitors prevent activation of STAT1 and thus block transcription of the cytokine genetic information, so cytokine production is prevented. Less inflammation-promoting cytokines, less inflammation.

Transcription factors and their sub-units regulate which particular genes have their information transcribed. The team found that JAK inhibitors partially interfered with one such transcription factor called NF-#B, which stands for nuclear factor kappa-light-chain-enhancer of activated B cells.

In a normal immune system response, NF-#B stimulates macrophages to produce pro-inflammatory cytokines. NF-#B directly interacts with the genes that code for pro-inflammatory cytokines. Blocking NF-#B would block the expression of genes that encode those pro-inflammatory cytokines.

Reducing Inflammatory Arthritis

Scientists use a model of arthritis to test in the laboratory how certain cellular actions and drug treatments might impact disease. One such model is known as K/BxN serum-transfer arthritis, which is a model of inflammatory arthritis, like RA. The K/BxN arthritis model used in the study is dependent on macrophages but not other cells of the immune system called lymphocytes.

The research team found that one of the drugs – CP-690,550 – strongly suppressed K/BxN arthritis, further demonstrating that JAK inhibitors are affecting macrophage response which would normally trigger inflammation.

Potential Unanticipated Side Effects

The study also showed that JAK inhibitors were augmenting the actions of some transcription factors. This augmented activity could indicate that some of the joint destruction aspects of RA might be affected by the drugs.

The team found that the levels of transcription factors nuclear factor of activated T-cells, (NFATc1) and cJun were actually increased. This increased transcription was followed by formation of osteoclast-like cells. Osteoclasts are cells that resorb bone that contributes to the morbidity of RA.

Increased inflammation in RA can destroy bone and cartilage in the joints. Increased osteoclast formation in test tube experiments with JAK inhibitors raises a cautionary note that if inflammation is not well controlled JAK inhibitors have the potential to actually increase the amount of bone resorption. Further studies will be required.

Tailoring Individual Anti-TNF Treatments

In the chronic inflammation of autoimmune diseases, the immune system is mistakenly reacting against the body itself, and keeping the macrophages active. Continually activated macrophages are continually expressing pro-inflammatory cytokines that are continually signaling for increased inflammation.

TNF’s central role in signaling that promotes the inflammatory process has made the cytokine an important target for RA drug therapies. The development of highly effective anti-TNF drugs ushered in a new era of therapeutic treatment in RA, helping effectively halt the condition’s chronic inflammation.

However, anti-TNF therapy is not without side effects, and not everyone benefits from the drugs. What’s more, long-term suppression of the immune system can leave people open to higher risk of serious infections.

This study shows, molecularly, how JAK inhibitors have their own ways of blocking macrophage activation and resulting genetic transcription. JAK inhibitors have different therapeutic targets than existing anti-TNF drugs, that can prevent TNF and other pro-inflammatory cytokines from being made.

The more that is known about how drugs specifically interact with the complex cellular networks and pathways involved in the immune system’s inflammatory processes, the more treatments can be refined to help individual patients experience reduction in inflammation with least side effects and best quality of life. These new findings about key cellular processes of a new class of drugs can help doctors tailor therapies for individual patients, helping stop the chronic inflammation of RA in ways that can best support long term health.

Study Published in Arthritis & Rheumatism, online in advance of publication, August 31, 2012.

HSS Authors
Anna Yarilina MD, PhD
Kai Xu
Chunhin Chan
Lionel B. Ivashkiv MD
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