Processing of precursor interleukin 1 beta and inflammatory disease.

Area of Science:

• Biochemistry and Molecular Biology
• Immunology
• Inflammation Research

Background:

• Interleukin 1 beta (IL1 beta) is a key cytokine in inflammatory responses.
• IL1 beta is initially synthesized as an inactive 31-kDa precursor.
• Processing of IL1 beta precursor to its active form is crucial for its function.

Purpose of the Study:

• To investigate the role of specific proteases in processing the IL1 beta precursor.
• To identify the proteases responsible for IL1 beta precursor activation at inflammatory sites.
• To compare in vitro protease activity with in vivo processing observed in patient samples.

Main Methods:

• Recombinant pro-IL1 beta was used as a substrate for protease digestion.
• Protease activity was assessed using elastase, cathepsin G, and collagenase.
• Amino-terminal sequencing was performed on processed IL1 beta to determine cleavage sites.
• Processing activity was analyzed in synovial fluid and bronchoalveolar lavage fluid from patients.

Main Results:

• Elastase, cathepsin G, and collagenase effectively cleaved the inactive IL1 beta precursor into an active form.
• The active IL1 beta generated by these proteases was similar in size and activity to mature IL1 beta.
• Cleavage occurred at distinct sites, yielding active IL1 beta with minor variations in amino-terminus.
• Inflammatory fluids from patients with inflammatory polyarthritis and sarcoidosis showed IL1 beta processing activity.
• This activity correlated with the presence of elastase and/or cathepsin G in the fluids.

Conclusions:

• Proteases such as elastase and cathepsin G, found at inflammatory sites, can process and activate secreted IL1 beta precursor.
• This mechanism provides a pathway for generating active IL1 beta in vivo during inflammatory conditions.
• The findings highlight the importance of protease activity in regulating IL1 beta's role in inflammation.