MECHANICAL DEFORMATION PROMOTES SECRETION OF IL-1-ALPHA AND IL-1 RECEPTOR ANTAGONIST

Both IL-1 alpha and IL-1 beta lack an N terminus secretory sequence, a nd the mechanism of secretion of these pleiotropic cytokines is incomp letely understood, The epidermis contains large quantities of IL-1 alp ha in keratinocytes, which may play a role in inducing endothelial adh esion molecules and promoting extravasation of leukocytes. Here we rep ort that mechanical deformation of human keratinocytes leads to rapid release of IL-1 alpha; possibly through transient disruptions in the p lasma membrane. Using a device that precisely controls the amplitude o f strain on the culture substrate, we found by pulse-chase analysis. W estern analysis, and ELISA that the release of IL-1 alpha is dependent on the amplitude of the strain, A cyclic strain of 14% released a sma ll but significant quantity of IL-1 alpha, while strains of 33% releas ed 66 +/- 9% of cytoplasmic IL-1 alpha over 1 h (p < 0.001). Release o f IL-1 alpha was accompanied by rapid release of large stores of IL-1R antagonist, approximately 25 to 30 times greater by mass than the qua ntity of IL-1 alpha released, but only a small fraction of cytoplasmic lactate dehydrogenase, Media conditioned by mechanically stimulated k eratinocytes induced expression of E-selectin by human vascular endoth elial cells; induction of E-selectin was completely inhibited by an Ab to IL-1 alpha. Therefore, mechanical strain promotes the secretion of IL-1 alpha, and deformation of keratinocytes in the epidermis may act ivate vascular endothelium through mechanically released IL-1 alpha, T his pathophysiologic mechanism may play a role in the anatomic localiz ation of some inflammatory skin diseases, such as psoriasis, which occ urs more commonly in locations where the dermis is subjected to repeti tive stretch or trauma.