Th1 and Th2 cytokines differentially regulate the transformation of Kupffer cells into multinucleated giant cells but similarly enhance the Kupffer cell-induced hepatic stellate cell proliferation

To investigate the effects of T-helper cytokines on Kupffer cells (KCs), the effects of interferon-gamma (IFN-gamma; Th1 cytokine) and interleukin-4 (IL-4; Th2 cytokine) on KC morphology and their role in modulating the growth of hepatic stellate cells (HSCs) were examined. Fluorescence microscopic and electron microscopic data demonstrated that IL-4 transforms rat KCs into multinucleated giant cells (MGCs) in vitro. This transformation was inhibited by the addition of anti-ICAM-1 and anti-CD18 monoclonal antibodies. In addition, IL-4-induced KC transformation was suppressed by the presence of IFN-gamma. The formation of mouse hepatic MGCs was also demonstrated in vivo by the intraperitoneal injection of recombinant mouse IL-4. Although the presence of MGCs was found in all five out of five livers from IL-4-treated Th2-dominant BALB/c mice, but it was in only two out of five livers from IL-4-treated Th1-dominant C57BL/6 mice. In addition, fewer MGCs were found in the liver of C57BL/6 mice. In contrast, IFN-gamma treatment did not form hepatic MGCs in mice at all. The growth of HSCs in vitro was significantly increased by the addition of culture supernatant from lipopolysaccharide-stimulated rat KCs. Pretreatment of the KCs with either IFN-gamma or IL-4 further enhanced the growth stimulation. These results suggest that IFN-gamma and IL-4 affect KC morphology differently, but that both Th1 and Th2 cytokines play a similar role in the modulation of HSC growth by Kupffer cells in the presence of lipopolysaccharide.