Localization and Expression of CCR3 and CCR5 by Interleukin-1β in the RIN-5AH Insulin-Producing Model System: A Protective Mechanism involving Down-Regulation of Chemokine Receptors

Context and objective The inflammatory cytokine interleukin-1β has been considered to be an immune effector molecule in insulin dependent diabetes mellitus. As such, we examined its role on chemokine receptors which, when expressed in the pancreas, have also been associated with the development of type I autoimmune diabetes. Design and main outcome measures The presence of membrane and cytoplasmic levels of CCR3 and CCR5 expression is assessed by immunofluorescence in control and interleukin-1β-treated RIN-5AH cells. The cytoplasmic expression is also shown by confocal microscopy as assessed by the brightness of the cells whereas enzyme-linked immunosorbent assay detects secreted CCR3 and CCR5 molecules by comparing optical density values as these derive from the control and the treated cells. Cell-fractionation experiments show the exact location of the intracellular pools of the chemokine receptors by using the rab7 monoclonal antibody as a guiding molecule. Results Interleukin-1β down-regulates constitutively expressed surface CCR3 and CCR5 levels implying receptor internalization for re-utilization or destruction, secretion or both. Cytoplasmic immunofluorescence and confocal microscopy demonstrate cellular retention of chemokine receptors by interleukin-1β which may be released in the absence of interleukin-1β as assessed by enzyme-linked immunosorbent assay. Finally, cell-fractionation shows the presence of bothreceptors in endosomes exhibiting an increasing density after interleukin-1β treatment. Conclusions Given the association of chemokine receptors with progression to diabetes, it appears that interleukin-1β- induced down-regulation of CCR3 and CCR5 promotes a protective mechanism against cellular destruction. The major role of interleukin-1β is to maintain these molecules within the endosomes. Thus, interleukin-1β modulates the movement and the expression of constitutively expressed chemokine receptors and does not accentuate the totaldestructive effect suffered by the cells.


Simon Vassiliadis, Vassiliki Balabanidou, George K Papadopoulos, Irene Athanassakis

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