1. Production of IL-18BP by RPE cells is restricted to conditions such as exposure to inflammatory cytokines We reported in FY 2014 that RPE cells express constitutively IL-18. The physiological blocker of IL-18, i.e., IL-18 binding protein (IL-18BP), however, is not expressed constitutively by RPE cells. This expression pattern of the two cytokines is opposite to that of lymphoid cells (e.g., monocytes) in which IL-18BP, but not IL-18, is expressed constitutively. Further, RPE cells do not express 18BP even when activated for inflammasome production. Importantly, however, RPE cells do express IL-18BP when stimulated by interferon-gamma (IFN-g) or IL-27, products of inflammatory cells. These observations suggest that stimulation of RPE by endogenous inflammasome-generating agents, such as drusen or their components, yields IL-18 production, whereas during intracellular inflammatory conditions, with cells that produce IFN-g, or IL-27, RPE cells express IL-18BP as well. The selective production of only IL-18 by RPE cells in inflammasome-mediated conditions is in line with the notion that IL-18 inhibits angiogenesis, a possible outcome of this pathological condition. 2. Imbalance between of IL-18 and IL-18BP in patients with an autoinflammatory condition IL-18BP efficiently blocks the biological activity of IL-18 and normally, the levels of IL-18BP are higher than those of IL-18 in sera of healthy humans. A recent study carried out by S. Canna and coworkers at NIAMS, NIH (Nat Genet, 2014, 46:1140) described a novel pathologic condition in which an activating NLRC4 inflammasome mutation causes autoinflammation with recurrent macrophage activation syndrome (NLRC4-MAS). A feature observed in these patients is exceedingly high serum levels of IL-18 (10,000-20,000 pg/ml). We established a collaborative study with S. Canna in which we are measuring the levels of IL-18BP in sera of the NLRC4-MAS patients, as well as patients with other autoinflammatory conditions and healthy controls. We have examined serum samples of 9 normal donor and 43 serum samples of patients. The levels of serum IL-18BP in the controls was in line with reported studies, i.e., 2,000-3,000 pg/ml and such normal levels were measured in the majority of tested patients. Importantly, no correlation was found between the serum levels of IL-18BP and of IL-18, thus resulting in high levels of free IL-18 in the tested patients. 3. High levels of serum IL-18 do not affect the retinae in patients with a novel autoinflammatory condition The function/activity of IL-18 in eyes with age-related macular degeneration (AMD) is a highly contested issue. The group of J. Ambati presents data indicating the cytotoxic activity of IL-18 on RPE cells, a major pathological component of dry AMD, whereas the group of M. Campbell provides results showing that IL-18 is capable of inhibiting angiogenesis, the main pathogenic mechanism of wet AMD. The former notion was recently supported by an observation that serum levels of IL-18 in patients with AMD were significantly higher in patients with dry AMD than in their controls (80 pg/ml vs 50 pg/ml) (Ijima et al., IOVS, 2014, 55:6673). The serum levels of IL-18 in patients with NLRC4-MAS, as reported in the study by S. Canna et al., mentioned above (10,000-20,000 pg/ml), obviously exceeded by far the levels in the mentioned cases with dry AMD. The NLRC4-MAS patients made it possible, therefore, to examine the effects of exceedingly high levels of serum IL-18 on patient retinae. Ophthalmological analysis of eyes of NLRC4-MAS patients revealed no abnormalities in the retinae of these patients, thus essentially ruling out the possibility that high levels of circulating IL-18 play a role in the pathogenesis of dry AMD. (The ophthalmological analyses of the patients, identified by S. Canna, were performed by H.N. Sen and R.B. Nussenblatt).
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| Shi, Guangpu; Chen, Siqi; Wandu, Wambui S et al. (2015) Inflammasomes Induced by 7-Ketocholesterol and Other Stimuli in RPE and in Bone Marrow-Derived Cells Differ Markedly in Their Production of IL-1? and IL-18. Invest Ophthalmol Vis Sci 56:1658-64 |
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