Ординатура / Офтальмология / Английские материалы / Mechanisms of the Glaucomas_Shields, Tombran-Tink, Barnstable_2008

dispersion of the iris and subsequent pathogenesis in this mouse model of pigmentary glaucoma.

IL-18 increases the production of activated forms of MMP-2 as well as the production of pro-MMP-2 (61). In human myeloid leukemia cell line HL-60, IL-18 stimulates the MMP-9 gene and protein expression, which in turn degrades extracellular matrix (71). In the U937 cell line, IL-18 enhanced MMP-2 expression whereas TNFled to the elevation of MMP-9 (72). Exogenous addition of IL-18 induced macrophages to express MMPs, whereas neutralization of IL-18 to a lesser extent reduced MMP production (73). In ocular disease, cytokines can alter the activity of MMPs or lead to an imbalance between MMPs and TIMPs (74–76). However, the role of IL-18 in the regulation of MMPs expression in the eye remains unknown. Because IL-18 can up-regulate MMP expression in many cell and tissue types, the possibility that the increased expression of MMPs may be initiated by IL-18 in the iris/ciliary body in the eye of DBA/2J mice requires further clarification. We currently do not have any reasonable explanation for the significance of the increased MMP-2 expression or activity found in aqueous humor in DBA/2J mice. This may relate to a subsequent alteration in response to chronic inflammation.

Activation of MAPK and NF- B Signaling in the Iris of the DBA/2J Mouse

MAPK signaling plays an important role in inflammatory processes (51). MAPK is activated and involved in the pathogenesis of human autoimmune diseases, including the sialoadenitis of Sjögren’s syndrome (52) and rheumatoid arthritis (53). IL-18 is an important autoimmune mediator (57). A role for MAPK in IL-18 signaling was recently suggested (27,58). Activation of the MAPK p38, extracellular signal-regulated kinases (ERK) p44 and p42 by IL-18 was detected in a human NK cell line (59). Our report showed that the phosphor-MAPK was increased whereas total MAPK protein level in the iris/ciliary body was not altered, suggesting that the MAPK-signaling pathway may be activated in the iris/ciliary body tissue of DBA/2J mice (21). In addition, the increase in the translocalization of NF- B from the cytoplasm to nuclei in iris/ciliary body tissue was observed using the electrophoretic mobility shift assay (21). NF- B is able to translocate to the nucleus to activate the transcription of genes related to immune or stress responses (77–79). NF- B DNA binding to target gene promoters is a major molecular genetic event in the inflammation processes through the expression of target genes that encode cytokines and chemokines, such as IL-1, IL-2, IL-6, IL-8, and TNF-, and that encode inflammatory enzymes, such as COX-2, and iNOS. IL-18 is known to promote the release of TNFand IFN- (45–47), and to up-regulate inducible NO synthase, stromelysin, COX-2, IL-8, IL-13, and MMP expression in many cells and tissues (48–50). Therefore, IL-18 may be involved in the regulation of specific pro-inflammatory cytokine expression participating in the development of a chronic, subclinical inflammation through activation of MAPK/NF- B-signaling pathways.

Increase in the Gene Expression and the Activity of Apoptotic Signaling Components in the Iris of the DBA/2J Mouse

Major advances have been made in our general understanding of apoptosis. Much of the detailed biochemistry of the final stages of the apoptotic cascade was eluci-

dated (80). Intrinsic apoptotic signals interfere with the activity of the anti-apoptosis protein bcl-2 or stimulate the synthesis of apoptosis promoting agents such as Bad, Bax, or Bak. When an apoptotic signal occurs within the cell, Bad binds and inhibits anti-apoptotic Bcl-2. This causes cytochrome C release from the mitochondria into the cytoplasm. The cytosolic cytochrome C is thought to activate caspases. Active caspases cleave numerous intracellular proteins and contribute to characteristic apoptotic morphology. Extrinsic apoptotic signals are mediated through death receptors of the TNF superfamily-like Fas, which triggers the activation of the initiator caspase- 8. It was found that complete Bax deficiency in DBA/2J mice has a protective effect against the elevation of IOP (81).

The iris disease in both human and mouse pigmentary glaucoma involves focal iris cell death and iris pigment epithelial atrophy, which lead to a radial slit-like pattern of iris transillumination (2,4,9). The mechanism(s) of iris cell death in this disease remain unknown. The development of intrinsic iris melanosomal toxicity and melaninassociated antigens for the iris disease in DBA/2J mice was proposed previously (19,26). Therefore, we used a multi-probe RNase protection assay to detect altered gene expression of intrinsic and extrinsic apoptotic signaling components in the iris/ciliary body of DBA/2J mice. We found that the expression of caspase-8, Fas, FADD, FAP, and FAF and TNFR genes increased in the iris/ciliary body of DBA/2J mice by 6 months of age (21). In addition, the activity of caspase-3 in the iris/ciliary body of DBA/2J mice significantly increased at 5 months and peaked by 6 months (21). It is known that IL-18 promotes the release of TNFand IFN- , and induces Fas– FasL-mediated cytotoxicity (45–47). Concurrent administration of IL-12 and IL-18 to mice induced epithelial apoptosis and caused serious atrophy in murine lacrimal glands (51). It is known that IL-18 is able to repress anti-apoptotic Bcl-2 and Bcl-XL gene expression, to activate caspase-8, caspase-3, and caspase-9, and to promote Fas–FasL- mediated cytotoxicity in many cell and tissue types (48–50). These data indicate that IL-18 may play a role in the degeneration of the iris through a Fas/caspase-mediated mechanism in DBA/2J mice. It is highly possible that increased expression of IL-18 in the iris is an important risk factor in the disease susceptibility and may cause iris pigment epithelial cell degeneration through apoptotic mechanism as shown in Fig. 7. The unhealthy or degenerated iris pigment epithelial cells in addition to mechanical zonular-pigment epithelial interaction (iris’s rubbing against the zonules or lens) may cause iris damage leading to pigment dispersion and eventually glaucoma that is observed in DBA/2J mice.

IL-18-DEFICIENT DBA/2J MICE

As mentioned in the earlier section “the role of IL-18 in the eye”, we found increased expression of IL-18 in the iris/ciliary body and the aqueous humor of 3-month-old DBA/2J mice (21). This increase preceded the onset of clinical evidence of pigmentary glaucoma. Interpreting our data in light of recent studies showing the possible development of intrinsic iris melanosomal toxicity and melanin-associated antigens in the eye of DBA/2J mice (19) has led to the hypothesis that an increase in IL-18 expression in the iris/ciliary body is an important risk factor that may combine with mechanical zonular-pigment epithelial interactions to cause iris damage, pigment dispersion, and

Fig. 7. Hypothetic apoptotic signaling involving interleukin (IL)-18-mediated iris degeneration. i) tumor necrosis factor (TNF)- /TNF-R/TRADD/caspase-8/caspase-3. ii) FAS- ligand/FAS/RIP/capsase-2/caspase-3. iii) FAS-ligand/FAS/FADD/caspase-8/caspase-3. iv) Trail-ligand/TRAIL-R/caspase-8/caspase-3. v) Bid/Bad/cytochrome c/caspase-9/caspase-3.

eventually glaucoma. Neutralization of IL-18 by systemic administration of the IL-18- BP or anti-IL-18 antibody was effective in reducing the severity of several systemic diseases (55,82). Because the glaucomatous phenotype develops in aging DBA/2J mice, the time course of the disease may take months to develop. Because long-term systemic or local administration of the IL-18-BP or antibody is not feasible, an IL-18 knockout mouse on the DBA/2J background was developed to examine the role of IL-18 in the pathogenesis of pigmentary glaucoma.

Generation of IL-18-Deficient DBA/2J Mice

The IL-18-deficient C57BL/6J mice are viable, fertile, normal in size, and do not display any gross physical or behavioral abnormalities (83). To generate ILdeficient mice on the DBA/2J genetic background, DBA/2J mice with both Tyrp1b/b and GpnmbR150x/R150x mutations were crossed with IL-18−/− mice on the C57BL/6J background. The resultant F1 mice were then backcrossed to DBA/2J mice to produce the F2 generation. Genotyping of the Tyrp1b/b and the Tyrp1b/b-GpnmbR150x/R150x DBA/2J mice confirmed the presence of the appropriate gene mutations and backcrossing continued through six generations. The resultant DBA/2J mice were more than 98% pure. Then, we intercrossed the F6 heterozygous IL-18+/− mice to produce the F6 generation of the IL-18−/−-DBA/2J, the IL-18+/−-DBA/2J, and the IL-18+/+-DBA/2J mice. To confirm the loss of the IL-18 gene in the F6 generation of IL-18−/−-DBA/2J mice, the IL-18−/− locus was genotyped by using PCR. As shown in Fig. 8A, IL-18-deficient C57BL/6J mice have a band at 280 bp, whereas the DBA/2J

Fig. 10. Morphological findings from the F6 generation of the interleukin (IL)-18−/−- DBA/2J and the IL-18+/+-DBA/2J mice. (A–D) Coat color alteration. A complete coat color change is seen in the F6 generation of the IL-18+/+-DBA/2J and the IL-18−/−-DBA/2J mice. (E–H) Iris and anterior chamber images show significant iris atrophy in the DBA/2J and the F6 generation of the IL-18+/+-DBA/2J mice but not in the F6 generation of the IL-18−/−-DBA/2J mice. (I–L) Retinal cross-sections showing loss of retinal ganglion cells in the DBA/2J and the F6 generation of the IL-18+/+-DBA/2J mice but not in the F6 generation of the IL-18−/−DBA/2J mice. The DBA/2J mouse is the only strain that shows many clinical features in common with pigmentary glaucoma in humans.

compared among the IL-18−/−-DBA/2J, the IL-18+/+-DBA/2J, the IL-18−/−-C57BL/6J, and the IL-18+/+-C57BL/6J mice. Slit light examination showed clear iris atrophy in the DBA/2J and the IL-18+/+-DBA/2J mice (see Fig. 10E and H). The iris and anterior chamber of the IL-18−/−-DBA/2J were normal in appearance (see Fig. 10G). Histology of retinal cross-sections showed a dramatic loss of retinal ganglion cells in the DBA/2J mice (see Fig. 10I). Severe loss of ganglion cells was also observed in the IL-18+/+- DBA/2J mice (see Fig. 10L). Interestingly, most of retinal ganglion cells of the IL-18−/−- DBA/2J mice were preserved (see Fig. 10K) compared with the IL-18+/+-DBA/2J littermates. The distribution and density of the retinal ganglion cells in the IL-18−/−-DBA/2J mice were similar to that of the IL-18−/−-C57BL/6J mice (see Fig. 10J).

IL-18 Deficiency in DBA/2J Mice Prevents the Development of Glaucomatous Phenotype

The spatial vision and contrast sensitivity of the IL-18−/−-DBA/2J and the IL-18+/+- DBA/2J mice, as well as the DBA/2J, the IL-18−/−-C57BL/6J, and the C57BL/6J control mice were measured at 6 months of age. The spatial vision acuity of the DBA/2J

CONCLUSION

To date, there are no published investigations to evaluate possible localized immune abnormalities of the aqueous, iris, or trabecular meshwork in human eyes with pigmentary glaucoma. The possible subtle role that immune abnormalities may play in the etiology of human pigmentary glaucoma remains unknown. Despite the recent studies of human pigmentary glaucoma that have focused on the mechanical theories, research to understand the role of autoimmune dysregulation in the development of this disease in animal models has made significant progress. Yet, much remains to be explored. We have examined the correlation of IL-18 expression to the elevated IOP, to the ganglion cell and vision loss, and to the other biochemical alterations in the eyes of DBA/2J mice. Our findings from the IL-18−/−-DBA/2J mice revealed normal iris appearance, no retinal ganglion cell loss, normal IOP, and normal visual function. These indicate that the increased expression of IL-18 in the eye of DBA/2J mice may play a critical role in the pathogenesis of mouse pigmentary glaucoma. We predict that when the role of the inflammatory mechanism in glaucoma is unveiled, new therapeutic agents will emerge to complement and synergize with other therapeutic paradigms.

ACKNOWLEDGMENTS

The research summarized in this chapter is supported by NIH grant P20 RR017703 from the COBRE program of the National Center for Research Resources and by an unrestricted grant from RPB to the department of Ophthalmology, University of Oklahoma Health Sciences Center.

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