Comfort Kristen K, Haugh Jason M
Department of Chemical and Biomolecular Engineering, North Carolina State University, Box 7905, Raleigh, NC 27695, USA.
Cell Mol Bioeng. 2008 Sep;1(2-3). doi: 10.1007/s12195-008-0015-9.
The cytokines interleukin (IL)-2 and IL-4 are important regulators of the adaptive immune response, due in part to their effects on clonal expansion and differentiation of T cells. When IL-2 and IL-4 are administered together, both antagonistic and synergistic effects have been reported, but little is known in general concerning the mechanisms underlying such combinatorial effects. We found evidence for both effects in the proliferation responses of the IL-2 and IL-4 responsive T cell line, HT-2; IL-4 delays the onset of cell growth yet ultimately allows a higher cell density to be achieved in static culture. At the level of signal transduction pathways, we found that IL-4 partially inhibits IL-2 receptor-mediated pathways (PI3K/Akt, Ras/Erk, and STAT5a/b) and does not prolong their transient kinetics. This mode of antagonism, but not the effects on cell proliferation, is overcome at higher concentrations of IL-2 that are sufficient to saturate the signaling responses. By comparison, IL-4-stimulated activation of STAT6 is unaffected by IL-2 and shows sustained kinetics, and we speculate that this or another IL-4 receptor-specific pathway is responsible for the effects of IL-4 on IL-2-stimulated proliferation. A possibly related observation is that IL-4 induces a dramatic cell adhesion phenotype.
细胞因子白细胞介素（IL）-2和IL-4是适应性免疫反应的重要调节因子，部分原因在于它们对T细胞克隆扩增和分化的影响。当同时给予IL-2和IL-4时，已报道了拮抗和协同作用，但对于这种联合作用的潜在机制总体上知之甚少。我们在对IL-2和IL-4有反应的T细胞系HT-2的增殖反应中发现了这两种作用的证据；IL-4延迟了细胞生长的起始，但最终在静态培养中能实现更高的细胞密度。在信号转导通路水平，我们发现IL-4部分抑制IL-2受体介导的通路（PI3K/Akt、Ras/Erk和STAT5a/b），且不延长其瞬时动力学。在足以使信号反应饱和的较高浓度IL-2下，这种拮抗模式而非对细胞增殖的影响被克服。相比之下，IL-4刺激的STAT6激活不受IL-2影响，并显示出持续的动力学，我们推测这种或另一种IL-4受体特异性通路负责IL-4对IL-2刺激的增殖的影响。一个可能相关的观察结果是，IL-4诱导出显著的细胞黏附表型。
