Phagocytosis of rod outer membrane segments by human retinal pigment epithelial cells increases nitric oxide production
Retinal pigment epithelial cells (RPE) are involved in the maintenance of normal photoreceptor cells in the retina by phagocytosis of spent rod and cone outer membrane segments. RPE cells demonstrate other macrophagic characteristics including the expression of inducible nitric oxide mRNA. The generation of nitric oxide (NO) by inducible nitric oxide synthase (iNOS) may be associated retinal diseases. Using cultured human RPE clonal cell line, we have shown that RPE cells produce micromolar amounts of NO in response to specific activating factors. Maximal NO production was seen in RPE cells pretreated with gamma interferon (γIFN) and interleukin-4 (IL-4) and then incubated in the presence of rod outer segments plus the double stranded polyribonucleotide polyinosinic-polycytidilic (Poly I:C). This effect was inhibitable by N-methyl-L-arginine (L-NMMA), indicating de novo production of NO. The combination of factors above was critical to NO induction since Poly I:C, IL-4 nor rod outer segment alone did not induce NO. Pretreatment with γIFN and IL-4 was also essential. Standard NO induction agents for rodent macrophage i.e., TNF, IL-1, IFN and LPS or combinations thereof, did not produce any detectable supernatant levels of NO. We have shown that NO is produced in RPE cells via a viral mediated pathway and not by the normal cytokine mediated pathway as previously reported. This finding may play an important role in retinal-associated diseases.
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