Trinchieri G, Wysocka M, D'Andrea A, Rengaraju M, Aste-Amezaga M, Kubin M, Valiante N M, Chehimi J
Wistar Institute, Philadelphia, PA 19104.
Prog Growth Factor Res. 1992;4(4):355-68. doi: 10.1016/0955-2235(92)90016-b.
Natural Killer cell Stimulatory Factor (NKSF) or interleukin-12 (IL-12) is a heterodimeric cytokine of 70 kDa formed by a heavy chain of 40 kDa (p40) and a light chain of 35 kDa (p35). Although it was originally identified and purified from the supernatant of Epstein-Barr virus-transformed B cell lines, it has been shown that among peripheral blood cells NKSF/IL-12 is predominantly produced by monocytes, with lower production by B cells and other accessory cells. The most powerful inducers of NKSF/IL-12 production are bacteria, bacterial products and parasites. In addition to the biologically active p70 heterodimer, the cells producing NKSF/IL-12 also secrete a large excess of monomeric p40, a molecule with no demonstrable biological activity. NKSF/IL-12 is active on T lymphocytes and NK cells on which it induces production of lymphokines, enhancement of cytotoxic activity and mitogenic effects. NKSF/IL-12 induces T and NK cells to produce IFN-gamma and synergizes with other IFN-gamma inducers in this effect. In vitro, and probably in vivo, NKSF/IL-12 is required for optimal IFN-gamma production. When human lymphocytes are stimulated with antigens in vitro, addition of exogenous NKSF/IL-12 to the culture induces differentiation of T helper type 1 (Th1) cells, whereas neutralization of endogenous NKSF/IL-12 with antibodies favors differentiation of Th2 cells. IFN-gamma, a product of Th1 cells, enhances NKSF/IL-12 production by mononuclear cells, whereas IL-10 and IL-4, products of Th2 cells, efficiently inhibit it. Therefore, NKSF/IL-12 appears to be an important inducer of Th1 responses produced by accessory cells during early antigenic stimulation and its production is regulated by a positive feedback mechanism mediated by Th1 cells through IFN-gamma and a negative one by Th2 cells through IL-10 and IL-4. The balance of IL-12 production versus IL-10 and IL-4 production early during an immune response might therefore be instrumental in determining Th1-type versus Th2-type immune responses. Because of this potential role of IL-12 during immune responses, our results demonstrating the impaired ability of HIV seropositive patients to produce NKSF/IL-12 in response to bacterial stimulation suggest that this defect in NKSF/IL-12 production might be a factor contributing to their immune depression.
自然杀伤细胞刺激因子（NKSF）或白细胞介素-12（IL-12）是一种70 kDa的异二聚体细胞因子，由一条40 kDa的重链（p40）和一条35 kDa的轻链（p35）组成。尽管它最初是从爱泼斯坦-巴尔病毒转化的B细胞系的上清液中鉴定和纯化出来的，但研究表明，在外周血细胞中，NKSF/IL-12主要由单核细胞产生，B细胞和其他辅助细胞产生较少。NKSF/IL-12产生的最有力诱导物是细菌、细菌产物和寄生虫。除了具有生物活性的p70异二聚体，产生NKSF/IL-12的细胞还分泌大量过量的单体p40，这是一种没有可证明生物活性的分子。NKSF/IL-12对T淋巴细胞和NK细胞有活性，可诱导它们产生淋巴因子、增强细胞毒性活性和有丝分裂作用。NKSF/IL-12诱导T细胞和NK细胞产生γ干扰素，并在这一效应中与其他γ干扰素诱导剂协同作用。在体外，可能在体内，最佳的γ干扰素产生需要NKSF/IL-12。当人淋巴细胞在体外被抗原刺激时，向培养物中添加外源性NKSF/IL-12可诱导1型辅助性T细胞（Th1）分化，而用抗体中和内源性NKSF/IL-则有利于Th2细胞分化。γ干扰素是Th1细胞的产物，可增强单核细胞产生NKSF/IL-12，而Th2细胞的产物IL-10和IL-4则可有效抑制其产生。因此，NKSF/IL-12似乎是早期抗原刺激期间辅助细胞产生Th1反应的重要诱导物，其产生受Th1细胞通过γ干扰素介导的正反馈机制和Th通过IL-10和IL-4介导的负反馈机制调节。因此，免疫反应早期IL-12产生与IL-10和IL-4产生之间的平衡可能有助于决定Th1型与Th2型免疫反应。由于IL-12在免疫反应中的这种潜在作用，我们的结果表明，HIV血清阳性患者对细菌刺激产生NKSF/IL-12的能力受损，这表明NKSF/IL-12产生的这种缺陷可能是导致他们免疫抑制的一个因素。
