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Table 1 Summary of the cytokines affected by PR3, with the PR3 action on cytokines and the resulting response. The processes relevant to the pathophysiology of COPD are highlighted in bold

From: Proteinase 3; a potential target in chronic obstructive pulmonary disease and other chronic inflammatory diseases

Cytokine

Role of PR3

Action of cytokine

References

Interleukin (IL)-1β

Proteolytically activates extracellular pro-forms to be cleaved into active counterparts by Caspase 1 in inflammasomes

• ↑ neutrophil activation and recruitment

• canonical NFκB signalling

• ↑ cyclooxygenases [44] and prostaglandin E production

• pushes towards T helper cell (Th)17 differentiation

[31, 54,55,56]

IL-18

• Induces interferon (IFN)-γ and Fas ligand, ↑ differentiation to Th1, Th2 or Th17 responses (dependant on accompanying signals)

[55, 57]

Tumour necrosis factor (TNF)-α

Cleaves precursor to bioactive form (via two hypothesised cleavage sites at Ala15-Leu16 or Val77-Arg78)

• Activates the caspase and MEK cascades, and PI-3-kinase and canonical NFκB pathway

• Activates Etk = ↑cellular adhesion, migration and propagation

• ↑ neutrophil chemotaxis

• Upregulation of pro-inflammatory genes e.g. IL-8, CCL2, CXCL10, COX-2, and pro-coagulants

• Recruits apoptosis-inhibiting molecules

• ↓ signalling by cIAP-mediated ubiquitination

[54, 58]

IL-6

Functionally inactivates and degrades the soluble IL-6 receptor (sIL-6R) – exact mechanisms unknown

• Disrupts trans-signalling activity

• Prevents apoptosis

• ↑ neutrophil recruitment and infiltration

[59, 60]

IL-8 (CXCL8)

Truncates stored IL-8 (77) into the 10-fold more potent chemo-attractant IL-8 (70) through cleavage of an Ala-Lys bond

• ↑ respiratory burst

• Potentiates inflammatory disease cycle

• Drives neutrophil chemotaxis

[61]

IL-17 (CTLA8)

Stimulation increases cytokine production

• Directs towards a dominant Th17 environment

• T cell hypo-responsiveness

[62]

IL-32

Processes activating cytokines IL-1β, TNF-α and IFN-γ directly or indirectly; cleaves IL-32 at IL-32α to a more bioactive form

• Activates canonical NFκB and MAPK cascades

• ↑ production of cytokines incl. TNF-α, IL-8 and CXCL2 production

[63, 64]