Interleukin-1{beta}-induced Reduction of CD44 S325 Phosphorylation in Human Epidermal Keratinocytes Promotes CD44 Homomeric Complexes and Binding to Ezrin, and Extended, Monocyte-adhesive Hyaluronan Coats [Cell Biology]

March 25th, 2015 by Jokela, T., Oikari, S., Takabe, P., Rilla, K., Karna, R., Tammi, M., Tammi, R.

The proinflammatory cytokine Interleukin-1β (Il-1β) attracts leukocytes to sites of inflammation. One of the recruitment mechanisms involves the formation of extended, hyaluronan-rich pericellular coats on local fibroblasts, endothelial cells, and epithelial cells. In the present work we studied how Il-1β turns on the monocyte adhesion of the hyaluronan coat on human keratinocytes. Il-1β did not influence hyaluronan synthesis or increase the amount of pericellular hyaluronan in these cells. Instead, we found that the increase in the hyaluronan-dependent monocyte binding was associated with the CD44 of the keratinocytes. While Il-1β caused a small increase in the total amount of CD44, a more marked impact was the decrease of CD44 phosphorylation at serine 325 (S325). At the same time, Il-1β increased the association of CD44 with ezrin, and complex formation of CD44 with itself. Treatment of keratinocyte cultures with KN93, an inhibitor of calmodulin kinase 2 (CAMKII), known to phosphorylate S325 in CD44, caused similar effects as Il-1β, i.e. homomerisation of CD44 and its association with ezrin, and resulted in increased monocyte binding to keratinocytes in a hyaluronan-dependent way. Overexpression of wild type CD44 standard form, but not a corresponding CD44 mutant mimicking the S325 phosphorylated form, was able to induce monocyte binding to keratinocytes. In conclusion, treatment of human keratinocytes with Il-1β changes the structure of their hyaluronan coat by influencing the amount, post-translational modification, and cytoskeletal association of CD44, thus enhancing monocyte retention on keratinocytes.
  • Posted in Journal of Biological Chemistry, Publications
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