PKCδ-IRAK1 axis regulates oxidized LDL-induced IL-1β production in monocytes

Area of Science:

• Immunology
• Cell Biology
• Molecular Biology

Background:

• Oxidized low-density lipoprotein (Ox-LDL) is implicated in atherosclerosis and inflammation.
• Interleukin-1 beta (IL-1β) is a key pro-inflammatory cytokine.
• The signaling pathways regulating Ox-LDL-induced IL-1β production are not fully elucidated.

Purpose of the Study:

• To investigate the roles of interleukin (IL)-1 receptor-associated kinase (IRAK) and protein kinase C (PKC) in Ox-LDL-induced monocyte IL-1β production.
• To identify the specific signaling molecules and receptors involved in this process.

Main Methods:

• Utilized THP1 cells and primary human monocytes.
• Employed siRNA and pharmacological inhibitors to block specific signaling molecules (e.g., IRAK1/4, PKCδ, JNK, NADPH oxidase).
• Assessed protein expression, kinase activity, phosphorylation, cytokine production, and transcription factor activation (AP-1).
• Analyzed plasma from patients with systemic inflammatory response syndrome (SIRS).

Main Results:

• Ox-LDL induced IL-1β secretion, IRAK1 activity, CD36 expression, PKCδ-JNK1 phosphorylation, and AP-1 activation in THP1 cells.
• IRAK1/4, NADPH oxidase, and JNK inhibition attenuated Ox-LDL-induced IL-1β production.
• PKCδ siRNA reduced IRAK1 activity, JNK phosphorylation, and AP-1 activation.
• CD36, TLR2, TLR4, and TLR6 were involved in Ox-LDL-induced signaling in THP1 macrophages and primary monocytes.
• Ox-LDL and IL-1β levels correlated with disease severity in SIRS patients.

Conclusions:

• The PKCδ-IRAK1-JNK1-AP-1 axis plays a critical role in Ox-LDL-induced IL-1β production.
• CD36, TLR2, TLR4, and TLR6 act as receptors mediating this response.
• These findings highlight a key inflammatory pathway relevant to Ox-LDL-associated diseases.