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D. WuDunn, A. McMahon, J. Haydon; TNF-Alpha Secretion May Mediate Mechanical Stretch-Induced Stress Response in Trabecular Meshwork Cells. Invest. Ophthalmol. Vis. Sci. 2007;48(13):2075.
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We have previously shown that mechanical strain and interleukin-1 (IL-1) act synergistically to activate nuclear factor kappa B (NFΚB), a marker of the glaucomatous stress response, in cultured trabecular meshwork cells. We sought to determine if tumor necrosis factor alpha (TNFα) acts as a mediator of this stretch-induced response.
Human and bovine trabecular meshwork cells were subjected to up to 10% mechanical biaxial stretch in the presence of varying levels of IL-1α. Cells were also exposed to IL-1α during or after exposure to varying levels of TNFα. Activation of NFΚB was determined by visualization of NFΚB in the nucleus by immunofluorescence microscopy or ELISA of whole cell, nuclear, or cytoplasmic fractions. TNFα and IL-1α levels in response to mechanical strain were assayed by ELISA. Antibodies to TNFα were used to suppress the effect of secreted TNFα.
The combination of mechanical strain (5-10%) and subthreshold levels of IL-1α (human: <0.03 ng/ml; bovine: <0.5 ng/ml) resulted in significant NFΚB activation within 4 hours of onset. Neither strain nor subthreshold levels of IL-1α induced this response. Culture media from mechanically-strained human cells significantly enhanced NFΚB activation by IL-1α in non-strained cells. Mechanical strain does not appear to increase endogenous IL-1α secretion in human TM cells but does induce low level secretion of tumor necrosis factor alpha (TNF-α). TNF-α and IL-1α also act synergistically in NFΚB activation.
Mechanical strain can modulate the IL-1-induced NFΚB-mediated stress response that is characteristic of glaucomatous trabecular meshwork. This enhancing effect appears to be mediated by a substance or substances secreted by the strained cells. Endogenous interleukin-1α does not appear to be a mediating substance but tumor necrosis factor alpha is a prime candidate.
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