IFN-γ directly controls IL-33 protein level through a STAT1- and LMP2-dependent mechanism

Area of Science:

• Immunology
• Molecular Biology
• Cell Biology

Background:

• Interleukin-33 (IL-33) is implicated in various diseases, often alongside T-helper 1 (Th1) and T-helper 2 (Th2) immune responses.
• While IL-33 mRNA regulation is understood, the post-synthesis fate of IL-33 protein remains unclear.
• Understanding IL-33 protein stability is crucial for deciphering its role in immune pathology.

Purpose of the Study:

• To investigate the interplay between Interleukin-33 (IL-33), Interferon-gamma (IFN-γ), and Interleukin-4 (IL-4) proteins.
• To elucidate the mechanisms regulating IL-33 protein levels in response to other cytokines.
• To determine the cellular pathways involved in IFN-γ-mediated IL-33 protein down-regulation.

Main Methods:

• Recombinant replication-deficient adenoviruses were used for co-expression of IL-33 with IFN-γ or IL-4 in lung fibroblast cultures and in vivo.
• Protein levels were assessed following dual gene delivery and compared to single cytokine expression.
• Inhibition studies involved caspases, STAT1, and the LMP2 proteasome subunit using pharmacological agents, siRNA, or gene deficiency.

Main Results:

• Co-expression of IL-33 and IFN-γ suppressed both protein levels, while IL-33 and IL-4 co-expression led to mutual elevation.
• In vivo, IFN-γ attenuated IL-33 protein levels in the lungs, suggesting IFN-γ-induced protein degradation.
• IFN-γ-mediated IL-33 down-regulation involved STAT1 and the LMP2 proteasome subunit in a caspase-independent manner.

Conclusions:

• IFN-γ, IL-4, and IL-33 exhibit complex interactions influencing each other's protein stability.
• IFN-γ down-regulates IL-33 protein levels in pulmonary fibroblasts and lung tissue via a STAT1-dependent pathway.
• This down-regulation utilizes the LMP2 proteasome subunit non-canonically and independently of caspases, offering new insights into cytokine regulation.