Study shows immune signaling protein IL-40 is also involved in SSc

Levels tied to disease activity, digestive problems, inflammation and scarring
by Steve Bryson, PhD | August 5, 2025

The immune signaling protein interleukin-40, or IL-40, may be involved in developing systemic sclerosis (SSc), a study from the Czech Republic suggests.
Elevated levels of IL-40 were found in the bloodstream of adults with SSc and correlated with worse disease activity, digestive problems, and markers of inflammation and fibrosis. Although higher IL-40 levels were generally resistant to treatment in some patients, pre-treatment levels and reductions in IL-40 during treatment correlated with improvements in several clinical outcomes.

“These findings might pave the way for further research into IL-40, including it’s potential as a marker of early detection,” the researchers wrote in the study, “Serum IL-40 is elevated in systemic sclerosis and is linked to disease activity, gastrointestinal involvement, immune regulation and fibrotic processes,” which was published in Arthritis Research & Therapy.
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SSc, or scleroderma, is an autoimmune disease marked by the excessive production of collagen, a protein and the main component of scar tissue. Excess scar tissue formation, or fibrosis, builds up in the skin and internal organs, including the heart and blood vessels, the lungs, stomach, and kidneys, causing damage. The disease is thought to arise from an abnormal immune response that’s driven by the release of TGF-beta, a signaling protein that activates fibroblasts, the cells that produce collagen. Other immune signaling proteins altered in SSc include IL-4 and IL-6.

The role of IL-40 in scleroderma
IL-40 has emerged as a possible contributor to autoimmune inflammation, with increased levels found in the bloodstream in various autoimmune diseases, including rheumatoid arthritis, Sjögren’s disease, and lupus. Its production and release have also been associated with pro-fibrotic TGF-beta.
“Nevertheless, no data on the role of IL-40 in the [development] of SSc are available,” wrote the researchers, who investigated IL-40 levels in the blood and tissue of adults with and without SSc.

Blood tests showed the median level of IL-40 was significantly higher in 90 SSc patients than in 75 sex- and age-matched healthy people (2.78 vs. 1.32 nanograms/mL). Blood levels of IL-40 were similar between different types of SSc.

Elevated IL-40 was associated with increased disease activity, as assessed by the European Scleroderma Study Group (ESSG) score, and gastrointestinal involvement, particularly constipation and swallowing difficulties. It was also linked with high TGF-beta and the pro-inflammatory molecule IL-8.

While IL-40 production varied in skin biopsy samples from adults with and without SSc, there was a higher percentage of IL-40-positive cells in SSc samples than in controls.

Higher IL-40 levels with worse SSc
When the researchers examined the impact of immune-suppressing cyclophosphamide treatment on IL-40 levels among SSc patients with lung disease, no significant changes were seen after a year.

No significant change in blood IL-40 levels were detected after rituximab treatment in SSc patients with active progressive disease either. Still, pre-treatment levels of IL-40 predicted a treatment-related easing in shortness of breath and an improvement in function and physical quality of life. And decreases in IL-40 during treatment were linked to some inflammatory measures normalizing, and less diarrhea and fatigue.

The researchers also tested blood samples from 24 people with a higher risk of developing SSc, based on various signs and symptoms of the disease. Over an average follow-up of 3.6 years, 11 patients progressed to SSc and 13 didn’t.

As in confirmed SSc patients, the median IL-40 levels were significantly higher among those at risk of SSc than in healthy controls (2.23 vs. 1.32 nanograms/mL). Even so, no differences were seen between those who progressed and those who didn’t.

Finally, exposing immune cells isolated from SSc patients to different levels of IL-40 triggered the production of the pro-inflammatory signaling proteins IL-6 and MCP-1, along with the anti-inflammatory IL-10, in a dose-dependent manner. Conversely, the release of IL-40 from immune cells was induced by IL-4 and TGF-beta, but not IL-6.
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“This study demonstrates for the first time that IL-40 is likely involved in the SSc [development],” the researchers wrote. “IL-40 levels were elevated in both SSc patients and at-risk individuals compared to healthy controls, and were associated with disease activity and gastrointestinal involvement.” The researchers said their findings need to be validated in larger studies.