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Down-regulation by Interleukin 4 of Activation of Human Alveolar Macrophages to the Tumoricidal State¹

Third Department of Internal Medicine, The University of Tokushima School of Medicine, Kuramoto-cho, Tokushima 770, Japan

The effect of recombinant human interleukin 4 (IL-4) on the expression of antitumor activity of human alveolar macrophages (AM) obtained by bronchoalveolar lavage from healthy donors was examined. AM were incubated for 16 h in medium with various macrophage activators [lipopolysaccharide, des-methyl muramyldipeptide, Nocardia rubra cell wall skeleton, and heptanoyl--D-Glu-(L)-meso-,-A2pm(L)-D-AlaOH] in the presence or absence of IL-4, and then their tumoricidal activity was assayed by measuring ¹²⁵I-UdR release from human melanoma (A375) cells. The spontaneous tumoricidal activity of AM was slightly suppressed by IL-4 in 3 of 7 donors. Addition of IL-4 to cultures of AM with the activators resulted in dose-dependent suppression of AM-mediated cytotoxicity against A375 cells. IL-4 also inhibited AM-mediated cytotoxicity against A375-R cells, which are resistant to interleukin 1 (IL-1) and tumor necrosis factor , HT-29 colon cancer cells, and KB cells. IL-4 inhibited the early induction phase of AM activation. Pretreatment of AM with IL-4 also suppressed their expression of antitumor activity in response to lipopolysaccharide. IL-4 inhibited the production of monokines (IL-1 and tumor necrosis factor ) by AM at the protein and mRNA levels. These findings suggest that IL-4 may be important in vivo in the down-regulation of antitumor expression of AM in the lung by inhibiting the production of monokines and other killing mechanisms.

¹ This work was supported by a grant from the Ministry of Health and Welfare of Japan.

² To whom requests for reprints should be addressed, at Third Department of Internal Medicine, The University of Tokushima School of Medicine, Kuramotocho 3, Tokushima 770, Japan.

Received 5/13/91. Accepted 7/31/91.

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