Interleukin-17 enhances immunosuppression by mesenchymal stem cells

Area of Science:

• Immunology
• Cell Biology
• Stem Cell Research

Background:

• Interleukin-17 (IL-17) is a potent pro-inflammatory cytokine with diverse biological functions.
• Mesenchymal stem cells (MSCs) possess immunomodulatory and immunosuppressive capabilities.
• The interplay between IL-17 and MSCs in modulating immune responses is not fully understood.

Purpose of the Study:

• To investigate the effect of IL-17 on the immunosuppressive function of MSCs.
• To elucidate the molecular mechanisms underlying IL-17-mediated modulation of MSC immunosuppression.
• To evaluate the in vivo relevance of IL-17's role in MSC-mediated immunosuppression.

Main Methods:

• In vitro co-culture of MSCs with inflammatory cytokines (IFNγ, TNFα) and IL-17.
• Assessment of MSC immunosuppressive activity.
• Analysis of inducible nitric oxide synthase (iNOS) expression and function.
• Evaluation of AUF1 protein levels and mRNA stability.
• Concanavalin A (ConA)-induced hepatitis mouse model to assess in vivo effects.
• Experiments using auf1(-/-) MSCs.

Main Results:

• IL-17 significantly enhanced the immunosuppressive effect of MSCs induced by IFNγ and TNFα.
• This enhancement was dependent on the increased expression of iNOS in MSCs.
• IL-17 promoted MSC immunosuppression in vivo in a concanavalin A-induced hepatitis model, also via an iNOS-dependent mechanism.
• IL-17 increased mRNA stability of iNOS by modulating the protein level of AUF1.
• In the absence of AUF1, MSCs exhibited maximal immunosuppressive effects without IL-17 stimulation.

Conclusions:

• IL-17 plays a novel role in promoting MSC-mediated immunosuppression.
• The mechanism involves iNOS induction and is regulated by AUF1-mediated mRNA stability.
• These findings highlight a new therapeutic target for modulating immune responses involving MSCs.