Goldring M B, Krane S M
Department of Medicine, Harvard Medical School, Boston, Massachusetts.
J Biol Chem. 1987 Dec 5;262(34):16724-9.
Interleukin 1 (IL-1), a monocyte product, exerts a range of biological effects on nonimmune cells such as fibroblasts and chondrocytes including stimulation of synthesis and release of prostaglandin E2 (PGE2) and collagenase. We have previously shown that crude mononuclear cell-conditioned medium, which contains IL-1, also stimulates synthesis of types I and III collagens by human synovial and dermal fibroblasts and chondrocytes when the formation of PGE2, which inhibits collagen synthesis, is blocked by indomethacin. To determine whether IL-1 is responsible for the affects observed using crude monocyte-conditioned medium patterns of collagen synthesis in the three types of human cells in response to recombinant preparations of IL-1 were compared. Preincubation of chondrocytes or synovial fibroblasts with either murine (m)IL-1 alpha or human (h)IL-1 beta alone decreased synthesis of type I collagen and fibronectin. In contrast, when endogenous IL-1-stimulated PGE2 synthesis was blocked by indomethacin, an enhancing effect of IL-1 on synthesis of these matrix proteins was unmasked. The synthesis of type III collagen was enhanced by IL-1 to a greater extent than that of type I collagen in the presence of indomethacin. In human foreskin fibroblasts, which produced low levels of PGE2 even in the presence of IL-1, synthesis of types I and III collagens was increased by IL-1 either in the absence or presence of indomethacin. These cells were more responsive to the hIL-1 beta preparation than to the mIL-1 alpha (half-maximal stimulation of PGE2 production was observed at approximately 2.5-5 pM hIL-1 beta and at approximately 2.5 nM mIL-1 alpha). Levels of alpha 1 (I), alpha 2(I), and alpha 1(III) procollagen mRNAs measured by cytoplasmic dot hybridization paralleled the levels of collagens synthesized under the various experimental conditions. IL-1, therefore, is one product of monocytes capable of modulating collagen synthesis by these human mesenchymal cells probably by altering collagen gene expression. These studies suggest that both positive (IL-1) and negative (PGE2) signals may control collagen synthesis at the transcriptional level resulting in modulation of matrix turnover in cartilage, synovium, and skin.
白细胞介素1（IL-1）是一种单核细胞产物，对成纤维细胞和软骨细胞等非免疫细胞具有一系列生物学效应，包括刺激前列腺素E2（PGE2）和胶原酶的合成与释放。我们之前已经表明，含有IL-1的粗单核细胞条件培养基，当抑制胶原合成的PGE2的形成被吲哚美辛阻断时，也会刺激人滑膜和真皮成纤维细胞以及软骨细胞合成I型和III型胶原。为了确定IL-1是否是使用粗单核细胞条件培养基观察到的影响的原因，比较了三种人类细胞对重组IL-1制剂的胶原合成模式。单独用鼠（m）IL-1α或人（h）IL-1β预孵育软骨细胞或滑膜成纤维细胞会降低I型胶原和纤连蛋白的合成。相反，当内源性IL-1刺激的PGE2合成被吲哚美辛阻断时，IL-1对这些基质蛋白合成的增强作用就会显现出来。在吲哚美辛存在的情况下，IL-1对III型胶原合成的增强作用比对I型胶原的增强作用更大。在人包皮成纤维细胞中，即使在存在IL-1的情况下PGE2产生水平也很低，无论是否存在吲哚美辛，IL-1都会增加I型和III型胶原的合成。这些细胞对hIL-1β制剂的反应比对mIL-1α更敏感（在大约2.5 - 5 pM hIL-1β和大约2.5 nM mIL-1α时观察到PGE2产生的半最大刺激）。通过细胞质点杂交测量的α1（I）、α2（I）和α1（III）前胶原mRNA水平与在各种实验条件下合成的胶原水平平行。因此，IL-1是单核细胞的一种产物，可能通过改变胶原基因表达来调节这些人间充质细胞的胶原合成。这些研究表明，正向（IL-1）和负向（PGE2）信号可能在转录水平上控制胶原合成，从而导致软骨、滑膜和皮肤中基质周转的调节。
