Regulation of CD44 and its adhesive interactions with the extracellular matrix component, hyaluronan, by cytokines in normal and transformed human B lymphocytes.

Abstract

The interaction of CD44 with its ligand hyaluronan may play a vital role in many biological processes including leukocyte homing, activation and effector function, hematopoiesis as well as tumor formation and metastasis. This phenomenon may be influenced by the extracellular matrix molecules and cytokines present in the microenvironment. In this study, I investigated the regulation of CD44-HA interactions in normal human B cells and in a panel of B cell lines including: Epstein-Barr virus (EBV)-positive (+) and EBV-negative (-) Burkitt's lymphoma (BL) and lymphoblastoid B cell lines (B-LCL) generated by in vitro EBV-transformation of normal human B cells. Activation of purified B cells with bacterial lipopolysaccharide (LPS), pokeweed mitogen (PWM) or anti-IgM antibodies in the presence or absence of interleukin (IL)-2 or IL-4 failed to induce HA adhesiveness. Stimulation of B cells with PMA however, induced strong HA recognition. Amongst a variety of cytokines that influence B cell activation, proliferation and differentiation, only IFN-gamma and to some extent IL-4 inhibited PMA-induced CD44-HA interactions. IL-13, which shares components of the IL-4 receptor complex and exhibits many biological effects similar to that of IL-4, failed to inhibit HA recognition. EBV infection/transformation of B cells, an alternative method of B cell activation, enhanced the expression of CD44 H, and induced a number CD44 V isofoms but abrogated their ability to bind HA in response to PMA. Stimulation with PMA induced strong HA recognition in the EBV-positive BL cell line BL-30/B95-8, whereas LPS, Staphylococcus aureus Cowan strain I (SAC) or PWM failed to induce HA adhesion. Investigation of the effect of a similar panel of cytokines revealed that in contrast to its inhibitory effect in normal human B cells, IL-4 was capable of inducing HA recognition in BL30/B95-8 cells. IL-13, again, failed to influence HA recognition. In contrast, the ability to recognize HA following PMA or IL-4 stimulation was not observed in B-LCL cells, highlighting the stark contrast between BL30/B95-8 and B-LCL cells. To understand the effect of EBV on CD44 expression and HA recognition, we investigated a panel of EBV- and EBV+ B cell lines. EBV- BL cells failed to express CD44 and hence did not adhere to HA. A remarkable heterogeneity was revealed by the study of various EBV+ B cell lines with respect to CD44 isoform expression and their ability to recognize HA. BL-30/B95-8, Jijoye, IM and all the B-LCLs tested expressed CD44 H and CD44 V isoforms; yet, Jijoye and B-LCLs failed to recognize HA in response to PMA. In conclusion, these results establish that HA recognition and CD44 isoform expression are modulated as a consequence of the mode of human B cell activation, differentiation and/or state of transformation. (Abstract shortened by UMI.)