The latest research conducted by scientists from Virginia Commonwealth University (VCU) Massey Cancer Center may potentially change the current treatment and management options for several chronic metabolic disorders like rheumatoid arthritis, multiple sclerosis and malignant lesions. The researchers have discovered a new signaling pathway that plays a significant role in the pathogenesis of sterile inflammation.
According to the research, activation of a special transcriptional protein that modifies the activity of several genes (also known as interferon-regulatory factor 1 or IRF1) can play an integral part in inflammatory responses by increasing the activation and recruitment of mononuclear cells that elicit sterile inflammation in tissues. This is mainly accomplished by secretion and release of chemokines that attract mononuclear cells.
It has long been known that factors like IL-1 (interleukin 1) are key inducers of IRF-1 expression, yet the biological significance of this activity was unclear until recently. VCU scientists Sarah Spiegel and Tomasz Kordula (who are also affiliated with the Cancer Cell Signaling research program at the institute) identified a molecular signaling link between IRF-1 and IL-1 in the setting of sterile inflammation. The results of their work were published online in the peer reviewed journal Nature Immunology.
Inflammatory mediator, IL-1 is strongly linked to autoimmune and inflammatory conditions. The activation of IL-1 serves as a trigger to enhance biological activities like polyubiquitination. It is imperative to understand that the polyubiquitination process has several implications within the human body, and while one form is responsible for activation of protein degradation (also known as kiss of death); other forms (also referred to as K63-linked polyubiquitination) plays an important role in cellular signaling.
Kordula explained: “For the first time, we found that K63-linked polyubiquitination is a mechanism of IRF1 activation. Once activated, IRF1 induces potent chemokines that recruit immune cells to sites of sterile inflammation and promote healing.”
Co-leader of the Cancer Cell Signaling research program at Massey, Sara D. Lowry, who is also Professor of Oncology and VCU School of Medicine chair of the Department of Biochemistry and Molecular Biology along with Mann T. Kordula and Spiegel, conducted previous research to explore the link between cancer and chronic inflammation. It is suggested that exploring molecular mechanisms that trigger inflammation can help in managing malignancy and other inflammatory conditions as found in diseases like multiple sclerosis and rheumatoid arthritis.
Kordula commented: “As IRF1 affects the development of auto-inflammatory diseases, targeting this previously unrecognized IL-1-induced cascade may be clinically important in the future.”
The research scientists are currently planning to initiate animal studies by preparing IRF-1 laboratory models with cell-specific properties to identify the cellular types that are associated with the synthesis of chemokines under the influence of IRF-1 in the brain.