The immune system has a way of communicating through small proteins called interleukins, and interleukin-6 (IL-6) is one of these proteins that helps control the immune system’s response to infections and cancer. 

However, having too much or too little IL-6 can cause health problems, even without an infection. Too much IL-6 can cause inflammation and diseases like rheumatoid disease and cytokine storms, while not enough IL-6 can cause allergic disorders like atopic dermatitis, allergic airway inflammation, and hyper-IgE Syndrome.

Researchers at the University of Alabama at Birmingham have discovered a new mechanism by which a lack of IL-6 signaling creates a bias toward T helper 2 cells, which promote inflammation. T helper cells play a key role in the immune system, directing other cells to fight infection. The study, published in Cellular & Molecular Immunology, sheds light on how IL-6 signaling affects this process.

“Understanding how IL-6 contributes to suppress allergic sensitization may offer new strategies to prevent atopic disease in patients with deficient IL-6 signaling,” says Beatriz Leon, PhD an associate professor in the University of Alabama at Birmingham department of microbiology, in a release.

The researchers from the University of Alabama at Birmingham conducted an experiment on mice to understand how the interruption of IL-6 signaling creates a Th2 bias. They used a mouse model of allergic airway inflammation, which was induced by house dust mite allergen. In the experiment, mice were given intranasal allergen for three days and then exposed to the allergen again two weeks later to cause an allergic reaction. The researchers used T cells with different genetic backgrounds and biological inhibitors, such as antibodies against interleukins or interleukin receptors, in the experiment.

The researchers discovered that IL-6 signaling played a role in stopping allergen-specific T cells from turning into harmful Th2 cells. This mechanism worked alongside another previously identified mechanism involving interleukin-12 and the Tbet transcription factor, which also helped suppress commitment to the Th2 lineage.

The University of Alabama at Birmingham team discovered that, in their model, the commitment of harmful Th2 cell lineage required strong and extended signaling of interleukin-2, or IL-2, in cells that could not produce or respond to IL-6. However, in normal T cells, IL-6 inhibits the priming of Th2 cells by shutting down IL-2 signaling at the beginning of T-cell activation.

IL-6 increases the expression of a protein called SOCS3, which works as a negative regulator of certain cytokines that bind to receptors on the surface of cells. In the absence of SOCS3, these cytokines activate a signaling pathway called JAK/STAT, which changes the expression of certain genes. Cytokines include interleukins, interferons, and growth factors.

To support their proposed mechanism, the University of Alabama at Birmingham researchers used a selective inhibitor of JAK1, which is a protein involved in the JAK/STAT pathway, and found that it prevented the priming of harmful Th2 cells in cells that did not receive IL-6 signaling. This indicates that IL-6 suppression of the harmful Th2 bias works by inhibiting the JAK/STAT pathway.

The University of Alabama at Birmingham group also found that IL-6 had to act early—the first two days after T-cell priming with house dust mite allergen—to turn off IL-2 signaling.

The study shows that IL-6 signals are important for stopping the harmful Th2 response and preventing disease. The researchers believe this knowledge will help understand why some people have problems with their IL-6 signaling or don’t produce enough IL-6 due to environmental factors.