Abstract
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. Although 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. 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, known to phosphorylate Ser-325 in CD44, caused similar effects as IL-1β (i.e. homomerization 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 Ser-325-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.
Highlights
Interleukin-1 recruits leukocytes at the site of inflammation
We studied whether IL-1 exerts a similar effect in keratinocytes and how this CD44 is associated with the formation of the cytokine-induced, extended hyaluronan coats observed previously in these cells [26, 33]
IL-1 Increases CD44 Expression in Keratinocytes—Because it has been previously shown that IL-1 induces CD44 expression in several cell types (28 –32), we checked whether it exerts a similar effect on keratinocytes
Summary
Results: The interleukin-1-induced hyaluronan coat increased monocyte binding to keratinocytes through ezrin-associated CD44 homomers, enabled by reduced serine 325 phosphorylation. We studied whether IL-1 exerts a similar effect in keratinocytes and how this CD44 is associated with the formation of the cytokine-induced, extended hyaluronan coats observed previously in these cells [26, 33]. Our data show that besides slightly increasing CD44 expression, IL-1 blocked phosphorylation of CD44 at serine 325 while at the same time it increased CD44 homomeric complexes and binding of CD44 to ezrin These changes in CD44 phosphorylation, self-association, and cytoskeletal attachment apparently induced the extended hyaluronan coats that enhanced hyaluronan-dependent monocyte adhesion
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