Figure 2.

Secretion of IL-1β by monocytes in inflammatory diseases. Ligation of pattern recognition receptors, such as TLRs, induces expression of inactive pro-IL-1β; its cleavage by caspase-1 leads to mature IL-1β and secretion.109 Activation of caspase-1 requires assembly of the inflammasome, a multimolecular complex that includes NALP3 (cryopyrin) and the adaptor protein ASC.110 Exogenous ATP triggers the receptor P2X7 and its associated pore, pannexin-1, inducing a strong redox response (generation of ROS followed by upregulation of antioxidant systems) and facilitating assembly/activation of the inflammasome. TLR signaling also stimulates ROS generation and release of endogenous ATP, resulting in autocrine stimulation. NLRP3 mutant monocytes (from patients with cryopyrin-associated periodic syndromes) have altered basal and TLR-stimulated redox states, causing increased and abnormally fast secretion of LPS-stimulated IL-1β. IL-1 secretion is not increased further by ATP, seemingly due to depletion of this pathway after LPS alone.27,45,111 sJIA monocytes do not share this overall phenotype,45 but are resistant to ATP-enhanced IL-1 secretion.37 Anakinra treatment results in increased P2X7 transcripts in sJIA blood cells,37 suggesting that excess IL-1 activity leads to suppression of P2X7. IL-18 processing and secretion is similar to that of IL-1; however, pro-IL-18 is constitutively produced by monocytes. Abbreviations: ASC, apoptosis-associated speck-like protein containing a CARD; DAMP, damage-associated molecular pattern molecule; IL, interleukin; LPS, lipopolysaccharide; PAMP, pathogen-associated molecular pattern molecule; P2X7, P2X purinoceptor 7; ROS, reactive oxygen species; sJIA, systemic juvenile idiopathic arthritis; TLR, Toll-like receptor.