Alteration of inflammatory mediator secretion by peripheral blood mononuclear cells from patients with allergic rhinitis under the influence of a c-Jun N-terminal kinase inhibitor

Makarevich V.V., Kadushkin A.G., Tahanovich A.D., Dziadzichkina V.V.

Belarusian State Medical University, Minsk, Belarus

Introduction. The quality of life in patients with allergic rhinitis (AR) is significantly reduced. Current treatment methods do not achieve complete symptom control, making the search for alternative therapeutic approaches to AR an urgent priority.

Objective. To evaluate the effect of CC-401 (a c-Jun N-terminal kinase inhibitor) on the production of key inflammatory mediators by peripheral blood mononuclear cells (PBMCs) from AR patients.

Materials and Methods. A PBMC suspension was seeded into 24- or 96-well plates and incubated with CC-401 (at a concentration of 1 μM) and 4 recombinant proteins capable of inducing a type 2 immune response: interleukin-2 (IL-2, 20 U/mL), IL-25 (50 ng/mL), IL-33 (50 ng/mL), and thymic stromal lymphopoietin (TSLP, 50 ng/mL). Following 3 days of incubation, the production of IL-4, IL-5, and IL-13 in blood CD4+ and CD8+ T lymphocytes was analyzed using flow cytometry. The secretion levels of IL-4, IL-6, IL-8, IL-9, IL-13, IL-17A, tumor necrosis factor α (TNF-α), and interferon γ (IFN-γ) were measured in the PBMC supernatants.

Results. Under type 2 immune response-inducing conditions, CC-401 reduced the production of major Th2 and Th9 cytokines (IL-4, IL-9, and IL-13) by PBMCs. It also decreased the intracellular synthesis of IL-4, IL-5, and IL-13 by blood T helper cells and cytotoxic T lymphocytes. Furthermore, CC-401 increased IL-6 secretion, but had no effect on the production of Th1 and Th17 cytokines (TNF-α, IFN-γ, IL-17A), as well as IL-8 by PBMCs from AR patients.

Conclusion. The variable impact of CC-401 on different pathways of the cytokine cascade highlights the complexity of its immunomodulatory effect. This necessitates further study of its molecular mechanisms of action to assess its prospects for clinical application in the treatment of AR.