MicroRNA’s Role in Interferon’s Contribution to Inflammation
- MicroRNA-146a contributes to abnormal activation of the type I interferon pathway in human lupus by targeting the key signaling protein
Arthritis & Rheumatism, Volume 60, Issue 4, April 2009, pp. 1065–1075
What is the topic?
Interferons (IFNs) are proteins produced by immune cells when the immune system is activated. They send different instructions to cells depending on the needs of the immune response; this can lead to cells making certain inflammatory proteins. IFNs communicate with the cells by linking up with receptor proteins along the cell surface, the way a key fits into a lock. This action sends a signal into the cell that eventually either turns on or turns off the process we recognize as inflammation. The many specific ways in which each IFN group works -- the triggers that turn them on, the signals they send, the genes they regulate, the receptors they link up with -- is called a pathway.
For many years it has been well known that people with lupus have high levels of interferon alpha (IFN-α) in their blood, and recent studies have shown that an increased level of this interferon is associated with lupus disease activity and severity.
There are a number of signals and switches along the communication pathways that control inflammation, leading to the production of interferons and the ways in which interferons communicate with inflammatory cells. A group of very small substances called micro-RNA (miRNA) are thought to help in the regulation of inflammation in several ways. One way may be by interfering in the process by which genes (the genetic blueprint for the body) are translated into actual proteins (the machinery of the body). The miRNA may be able to do this by competing with the regular RNA that translates the instructions contained in the genes into the actual protein machinery. Also, miRNA may differ only slightly, yet have completely different functions. For example, some miRNA act like brakes on the IFN pathway, stopping it from being overactive. One of these brakes is called miRNA-146a.
What did the researchers hope to learn?
The researchers wanted to see if miRNA-146a levels in lupus patients were the same or different from healthy people, and if this was related to active lupus symptoms.
Who was studied?
Eighty-seven patients were studied: 52 with lupus, six with Behcet’s disease (another inflammatory disorder), and 29 healthy people as the control group. All of the people who participated in this study were Chinese.
Of the 52 lupus patients, there were 48 women and four men; 19 had inactive lupus and 33 had active lupus. Twenty-six of the lupus patients (19 with disease activity, 7 without) had a history of kidney involvement (lupus nephritis).
How was the study conducted?
First the researchers compared the levels of 156 different kinds of miRNA in a small group of lupus patients and healthy people to see if there were any differences.
The researchers then took blood samples from all 87 patients and compared levels of miRNA-146a in the three groups. They looked at differences in miRNA-146a levels among the lupus patients with active symptoms vs. those whose lupus was inactive and also looked at levels of miRNA-146a in relationship to the severity of the active lupus.
The researchers also measured whether the patients’ regular RNA had been activated to make three particular proteins that are produced when the type 1 IFN pathway is switched on. The researchers combined the levels of RNA for the three proteins for what they termed “the IFN score.” This score was then used to measure the degree to which the type 1 IFN pathway had been switched on.
The researchers did a number of laboratory experiments with cells from people who did or did not have lupus to see if they could learn how miRNA-146a might be specifically affecting the IFN pathway. In some cases they introduced very high levels of miRNA-146a into the cells and then observed the effects when the IFN pathway was activated. In other cases they used chemicals that blocked miRNA-146a to see what would happen.
What did the researchers find?
In the initial phase of the study, looking just at a few patients, the researchers found that miRNA-146a was one of seven kinds of miRNA that seemed to be found at levels at least six times lower in people with lupus than in people without lupus.
When looking at all of the participants in the study, the lupus group still had significantly lower levels of miRNA-146a than the other two groups. Since Behcet’s also is an inflammatory illness, this suggests that low miRNA-146a might be more specific to lupus. To support this idea, the researchers did not find that the levels of miRNA-146a in the lupus group were affected by any medications the patients were taking.
Lupus patients with inactive disease had lower levels of miRNA-146a than people without lupus, and the levels were even lower for those patients with active lupus. Average levels of miRNA-146a were also lower for lupus patients who had signs of active kidney disease (high amounts of protein in the urine) than for those with no signs of kidney involvement. The researchers observed that low miRNA-146a levels in these lupus patients were associated with high IFN scores, something that would be expected if miRNA-146a puts the brakes on the IFN pathway, and if lupus patients do not have good working brakes at that point.
Finally, the researchers found that high levels of miRNA-146a added into healthy patients’ immune cells caused less IFN to be made, suggesting this could be one way in which miRNA can put a brake on the interferon pathway .On the other hand, when chemicals were used to block the cells’ normal miRNA-146a, more interferons were made. They also were able to show that miRNA-146a also decreases the manufacture of some proteins that interferon turns on, showing that it can put the brakes on several parts of the interferon inflammatory response.
In summing up their findings, the researchers concluded that lower levels of miRNA-146a may contribute to inflammation in lupus patients. They also suggest that finding ways to increase miRNA-146a might offer new approaches for treating lupus.
What were the limitations of the study?
Although the researchers observed that, on average, lower miRNA-146a levels were associated with increased lupus activity, this may not be the case when looking at individual patients. Even within this study there were a number of patients with lower levels of miRNA-146a who did not have lupus. Similarly, there were patients with low levels of miRNA-146a whose lupus disease activity was less severe than those with higher miRNA-146a levels. This underscores the individuality of people and their immune systems. It should not be surprising that one approach or treatment may not help all people with lupus. Also, the researchers based some of their conclusions on experiments done on cells in a laboratory, changing the levels of miRNA-146a or blocking its actions. But looking at cells in isolation may not accurately reflect what is going on in the human body, where so many other factors may be at play.
What do the results mean for you?
This study suggests that the interplay between miRNA-146a levels and the type 1 interferon pathway may contribute to the inflammation of lupus. If so, measuring miRNA-146a levels may be of future use as a diagnostic test, or to see if people should be taking specific medicines that target the interferon pathway. (Several investigational products that target the IFN pathway are in clinical trials at this time.)