Abstract
Purpose: :
Caspase–1 seems to be an exception within the family of caspases, as it is involved both in the production of pro–inflammatory cytokines, such as interleukin–1ß (IL–1ß), and in apoptosis. Previously, we have shown that inhibition of caspase–1 prevents hyperglycemia–induced IL–1ß production and formation of acellular capillaries in retinas of diabetic and galactosemic mice. To investigate whether the beneficial effect of caspase–1 inhibition was strictly due to the subsequent inhibition of cytokine signaling, we used IL–1ß receptor knock–out (IL–1R1–/–) mice to assess the role of IL–1ß in diabetes–induced activation of pro–apoptotic caspases and diabetes–induced retinal pathology.
Methods: :
Wild type C57BL6 mice and IL–1R1–/– mice were made diabetic using streptozotocin. Normal mice served as control. At 5 months of diabetes, caspase activities were measured by incubating retinal lysates with fluorogenic substrates specific for the individual caspases. At 7 months of diabetes, formation of acellular capillaries was determined using the trypsin digest method.
Results: :
Diabetes significantly increased activities of several pro–apoptotic caspases, such as caspase–3,–6, and –8 in retinas of diabetic wild type animals compared to normal wild type animals. No diabetes–induced activation of pro–apoptotic caspases was detected in retinas of IL–1R1–/– mice. More importantly, IL–1R1–/– mice were completely protected from diabetes–induced retinal pathology. At 7 months of diabetes, the number of acellular capillaries/mm2 retina in the retina of diabetic IL–1R1–/– mice was 5.0 ± 1.3 similar to numbers found in retinas of normal IL–1R1–/– mice (3.4 ± 1.0) and normal wild type mice (4.8 ± 2.2) but significantly lower than numbers found in retinas of diabetic wild type mice (11.5 ± 3.9).
Conclusions: :
The results indicate that interleukin–1ß plays an important role in the development of diabetes–induced retinal pathology. Inhibition of the caspase–1/interleukin–1ß signaling pathway might represent a potential new strategy to inhibit capillary degeneration in diabetic retinopathy.
Keywords: diabetic retinopathy • cytokines/chemokines • inflammation