CYTOKINE INDUCTION OF THE ABILITY OF HUMAN MONOCYTE CD44 TO BIND HYALURONAN IS MEDIATED PRIMARILY BY TNF-ALPHA AND IS INHIBITED BY IL-4 ANDIL-13

Ligation of CD44 by hyaluronan (HA) is a key proinflammatory event tha t regulates lymphocyte and monocyte adhesion and cytokine production. While most immune cells express CD44, few immune cells constitutively bind HA. We have previously shown that monocyte CD44 acquires the abil ity to bind HA after in vitro culture of PBMC in human serum and, ther efore, we have investigated a series of human cytokines and bacterial LPS for their ability to induce and/or inhibit monocyte CD44 to bind H A. We found that IL-1 alpha, IL-1 beta, IL-3, granulocyte macrophage ( GM)-CSF, and TNF-alpha, as well as bacterial LPS, all directly induced peripheral blood monocytes to bind HA. In contrast, IL-2 and IL-15 up -regulated monocyte CD44 HA-binding in PBMC suspensions, but not in pu rified monocyte suspensions. An anti-TNF-alpha-neutralizing Ab inhibit ed IL-1 alpha-, IL-1 beta-, IL-3-, and GM-CSF-mediated monocyte HA bin ding. In addition, treatment of IL-2- and IL-15-stimulated PBMC cultur es with an anti-TNF-alpha Ab prevented IL-2- and IL-15-induced monocyt e HA binding, thus identifying TNF-alpha as a lymphocyte-derived facto r that acted on monocytes to induce HA binding. In contrast, IL-4 and IL-13 were potent inhibitors of monocyte CD44-HA binding induced by ei ther human serum or by IL-1 alpha, IL-1 beta, IL-3, GM-CSF, or TNF-alp ha. IL-10 had dual effects on monocyte CD44-HA binding. Alone, IL-10 i nduced HA binding to PBMC monocyte CD44, while in contrast, IL-10 inhi bited IL-l-induced monocyte CD44 binding to HA. Taken together, these studies identify a network of T cell and monocyte-derived cytokines th at regulate HA binding to peripheral blood monocyte CD44, primarily th rough TNF-alpha.