Understanding Isotretinoin's Anti-Inflammatory Mechanism Through Cytokine Levels

A recent study measured the changes in inflammatory cytokine levels in acne patients before and after taking isotretinoin to better understand the drug’s anti-inflammatory effects.¹ It was found that patients with moderate to severe acne experienced a reduction in IL-8, IL-36, and TWEAK levels.

Background

Oral isotretinoin is one of the most effective acne therapies on the market, although its exact mechanism of action isn’t fully explained. Previous data has proven that isotretinoin reduces serum TNF-α, IL-4, IL-17, and IFN-γ concentrations and influences TLR-2 expression at the same time. This expression in TLR-2 remained suppressed for at least 6 months after treatment ended, thus promoting long-term acne remission.²

Methods & Materials

The prospective, randomized, controlled trial took place from July 2024 to December 2024. It included 75 patients with acne and 25 healthy participants, all between the ages of 14 and 40. There were no gender or age variations between the 2 groups (p > 0.05).

Those with acne were diagnosed with moderate to severe disease at severity levels II (n = 23), III (n = 22), and IV (n = 21), according to the Pillsbury Classification. Every participant was also graded by a team of dermatologists using the Global Acne Grading System (GAGS). Scores were significantly lowered following 8 weeks of isotretinoin therapy.

All participants stopped taking oral acne-related medications for 30 days before the study began. Each received 20 mg a day of oral isotretinoin for 8 weeks. The investigators evaluated inflammatory cytokines (IL-8, IL-36, TNF-α, TSLP, and TWEAK) at the beginning and end of the study.

Results & Future Research

IL-8, IL-36, TNF-α, TSLP, and TWEAK levels were significantly higher in acne patients compared to healthy controls at the start of the study (p < 0.05). 

“This indicates that the patients have an imbalance in Th1/Th2 differentiation, which leads to abnormal cytokine secretion and exacerbates the inflammation seen in acne,” the investigators wrote.

After 8 weeks of isotretinoin treatment, IL-8, IL-36, and TWEAK levels greatly decreased (p < 0.05). TSLP decreased in all patients with acne but was only statistically significant in Grade II and Grade III patients. This pattern was similar in TNF serum levels. Grade IV patients with more severe acne may need longer treatment durations to get more meaningful results in these categories.

By decreasing IL-8 and IL-36 levels, isotretinoin may contribute to the resolution of inflammatory lesions and the interruption of the inflammation cycle, according to the authors. This is the first study to demonstrate that isotretinoin can suppress acne inflammation by reducing IL-36. Additionally, to some extent, the changes in TWEAK levels may inhibit the processes that lead to remodeling and acne scarring.

However, there was no correlation between the severity of acne and inflammatory cytokine levels, according to the Spearman analysis (p > 0.05). The small sample size, short follow-up period, and the lack of mild patients may have an impact on this. Thus, further research should investigate how isotretinoin affects different cytokine pathways based on acne severity levels and how this continues post-treatment.

References

1. Qi W, Wang R, Khasawneh SMS, Hui F, Liu Y. Levels of several inflammatory cytokines in acne patients before and after isotretinoin therapy: a randomized, controlled clinical trial. J Dermatolog Treat. 2025;36(1):2540594. doi:10.1080/09546634.2025.2540594

2. Karadag AS, Ertugrul DT, Bilgili SG, Takci Z, Akin KO, Calka O. Immunoregulatory effects of isotretinoin in patients with acne. Br J Dermatol. 2012;167(2):433-435. doi:10.1111/j.1365-2133.2012.10949.x