INTERACTION OF MONOCYTOID CELLS WITH THE MUCOSAL ADDRESSIN MADCAM-1 VIA THE INTEGRINS VLA-4 AND LPAM-1

The differentiation of myeloid cells into macrophages and granulocytes is accompanied by marked changes in adhesive phenotype. Here we seek to understand the regulation of expression and functionality of the VL A-4 (alpha 4 beta 1), LPAM-1 (alpha 4 beta 7) and HML-1 (alpha E beta 7) integrins on monocytes/macrophages and granulocytes, given that the se integrins including LFA-1 (alpha L beta 2) mediate the entry, reten tion and signalling events of pathogenic leucocytes within chronically inflamed tissues. Phorbol ester-induced monocytic differentiation of the promyelocyte cell line HL60 led to increases in the steady-state l evels of beta 2 and beta 7 mRNA transcripts, requiring a period of 10 and 24 h, respectively, of de novo protein synthesis, There was a para llel de novo expression of LPAM-1 on the cell surface, despite the fac t that alpha 4 mRNA transcripts were rapidly downregulated. At 72 h, H ML-1 was not coexpressed with LPAM-1 on HL60 cells, although it was we akly expressed on peripheral blood monocytes/macrophages after a prolo nged period of in vitro culture. Retinoic acid-induced granulocytic di fferentiation of HL60 cells led to the appearance of low levels of LPA M-1 at the cell surface. LPAM-1 was not found expressed on peripheral blood neutrophils, raising the possibility that it is transiently expr essed during granulocyte differentiation. In accord with the above fin dings, differentiated monocytes and HL60 cells bound to recombinant MA dCAM-1 in an alpha 4- and beta 7-integrin-dependent fashion, whereas a population of undifferentiated HL60 cells and Mn++-activated monocyte s bound in an alpha 4-integrin-dependent beta 7-integrin-independent m anner via VLA-4 expressed abundantly at all stages of differentiation. Four h after attachment, some of these VLA-4(+) LPAM-1(-) HL60 cells could be seen to start spreading. These findings suggest that MAdCAM-1 can bind to VLA-4 when LPAM-1 is absent, and thus has the potential t o recruit both VLA-4-bearing monocytes and VLA-4(+) LPAM-1(-) macropha ges into chronically inflamed tissues.