Role of transcriptional co-factor hints at possible inflammatory bowel disease treatment

December 12, 2017

Tokyo - Inflammatory bowel disease (IBD), including the two conditions ulcerative colitis and Crohn's disease, results in long-term inflammation of the gut and is associated with dysregulation of the immune system. However, it is notoriously difficult to determine the cause of IBD, although genetic and environmental factors are implicated. To better understand disease development, researchers have developed a mouse model in which gut inflammation is induced by addition of the chemical dextran sodium sulfate (DSS) to the drinking water of mice.

Mice lacking the MKL1 protein, which shuttles between cytoplasm and nucleus serving as a transcriptional co-factor of serum response factor, develop less-severe inflammation in the IBD model than control animals. This suggested that MKL1 has a role in IBD disease development, but the details of this were unclear. Researchers at Tokyo Medical and Dental University (TMDU) built on this knowledge by generating mice overexpressing human MKL1 in specific white blood cells. They revealed that MKL1 causes the development of inflammation by controlling white blood cell functions. Their findings were published in Scientific Reports.

The gut lining closest to the intestinal canal contains a layer of tissue including white blood cells known as macrophages, which are the scavengers of the immune system. These macrophages help maintain the gut equilibrium, and protect it from infection.

The TMDU researchers showed MKL1 is expressed at higher levels in the macrophages of mice treated with DSS than untreated mice. This strongly suggested a role for macrophage MKL1 in the development of IBD.

The team then developed mice that expressed high levels of human MKL1 specifically in their lineage of macrophages, which are large white blood cells regulating the immune system.

"We noticed that these transgenic mice had fewer proportion of macrophages and more monocytes in the lining of their colon wall than control mice," explains Jianbo An, lead author of the study. "Intestinal macrophages suppress inflammation as a part of their defensive immune response."

"Microscopic examination of the colons of DSS-treated transgenic mice revealed destruction of the epithelium and severe ulceration," corresponding author Akinori Kimura says. "This was accompanied by a massive influx of inflammatory cells. The fulminant pathology may result from mitigated anti-inflammatory property of macrophages."

As the overexpression of MKL1 worsens the development of IBD-associated inflammation, this suggests that targeting of the protein or gene has potential for the treatment of IBD, which currently has no cure.
-end-
The article, "MKL1 expressed in macrophages contributes to the development of murine colitis" was published in Scientific Reports at DOI:10.1038/s41598-017-13629-0.

Tokyo Medical and Dental University

Related Immune System Articles from Brightsurf:

How the immune system remembers viruses
For a person to acquire immunity to a disease, T cells must develop into memory cells after contact with the pathogen.

How does the immune system develop in the first days of life?
Researchers highlight the anti-inflammatory response taking place after birth and designed to shield the newborn from infection.

Memory training for the immune system
The immune system will memorize the pathogen after an infection and can therefore react promptly after reinfection with the same pathogen.

Immune system may have another job -- combatting depression
An inflammatory autoimmune response within the central nervous system similar to one linked to neurodegenerative diseases such as multiple sclerosis (MS) has also been found in the spinal fluid of healthy people, according to a new Yale-led study comparing immune system cells in the spinal fluid of MS patients and healthy subjects.

COVID-19: Immune system derails
Contrary to what has been generally assumed so far, a severe course of COVID-19 does not solely result in a strong immune reaction - rather, the immune response is caught in a continuous loop of activation and inhibition.

Immune cell steroids help tumours suppress the immune system, offering new drug targets
Tumours found to evade the immune system by telling immune cells to produce immunosuppressive steroids.

Immune system -- Knocked off balance
Instead of protecting us, the immune system can sometimes go awry, as in the case of autoimmune diseases and allergies.

Too much salt weakens the immune system
A high-salt diet is not only bad for one's blood pressure, but also for the immune system.

Parkinson's and the immune system
Mutations in the Parkin gene are a common cause of hereditary forms of Parkinson's disease.

How an immune system regulator shifts the balance of immune cells
Researchers have provided new insight on the role of cyclic AMP (cAMP) in regulating the immune response.

Read More: Immune System News and Immune System Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.