De Groot C J, Montagne L, Barten A D, Sminia P, Van Der Valk P
Graduate School Neurosciences, Academic Hospital Vrije Universiteit, Department of Pathology, Amsterdam, The Netherlands.
J Neuropathol Exp Neurol. 1999 Feb;58(2):174-87. doi: 10.1097/00005072-199902000-00007.
It is known that the pleiotropic cytokine transforming growth factor beta (TGF-beta) has a regulatory role in the process of tissue repair and remodelling following injury. As reports on these molecules in multiple sclerosis (MS) lesion with different lesional activity are rare, we studied the cellular localization of TGF-beta1, -beta2, and -beta3 isoforms, and TGF-beta receptor type I (TGF-betaR-I) and TGF-betaR-II expression by immunohistochemistry on postmortem brain tissue from MS and normal control cases. To validate the TGF-beta staining results we demonstrated that cultured human adult astrocytes that produce biological active TGF-beta2, and to a lesser extent TGF-beta1, were immunoreactive for all 3 TGF-beta isoforms. Moreover, at mRNA level TGF-beta1 was detected in MS and normal control brain tissue. In normal control brain tissue, TGF-beta isoforms were expressed in ramified microglia and TGF-beta2, and -beta3 on neuronal cells in the gray matter TGF-betaR-I and TGF-betaR-II expression was found on endothelial cells, astrocytes, microglia, and neurons. In active demyelinating MS lesions a strong to intense immunoreactivity was detected for all 3 TGF-beta isoforms in perivascular and parenchymal (foamy) macrophages and in hypertrophic astrocytes. Strong immunoreactivity for TGF-betaR-I and TGF-betaR-II was found on macrophages in both parenchymal and perivascular areas and on hypertrophic astrocytes and endothelial cells in active demyelinating MS lesions. In chronic active and inactive MS lesions, all 3 TGF-beta isoforms and their receptors were strongly expressed in hypertrophic astrocytes. Our findings strongly suggest that the expression of the various TGF-beta isoforms and their receptor types found in MS lesions with different cellular activity participate in reactive processes leading to the formation of chronic MS lesions.
众所周知，多效细胞因子转化生长因子β（TGF-β）在损伤后的组织修复和重塑过程中具有调节作用。由于关于这些分子在具有不同病变活性的多发性硬化症（MS）病变中的报道很少，我们通过免疫组织化学研究了TGF-β1、-β2和-β3亚型以及I型TGF-β受体（TGF-βR-I）和TGF-βR-II在MS和正常对照病例尸检脑组织中的细胞定位。为了验证TGF-β染色结果，我们证明了培养的产生生物活性TGF-β2以及少量TGF-β1的人成年星形胶质细胞对所有3种TGF-β亚型均具有免疫反应性。此外，在mRNA水平上，在MS和正常对照脑组织中均检测到TGF-β1。在正常对照脑组织中，TGF-β亚型在分支状小胶质细胞中表达，TGF-β2和-β3在灰质中的神经元细胞上表达，TGF-βR-I和TGF-βR-II在内皮细胞、星形胶质细胞、小胶质细胞和神经元上表达。在活动性脱髓鞘MS病变中，在血管周围和实质（泡沫状）巨噬细胞以及肥大星形胶质细胞中检测到所有3种TGF-β亚型的强至强烈免疫反应性。在实质和血管周围区域的巨噬细胞以及活动性脱髓鞘MS病变中的肥大星形胶质细胞和内皮细胞上发现了TGF-βR-I和TGF-βR-II的强免疫反应性。在慢性活动性和非活动性MS病变中，所有3种TGF-β亚型及其受体在肥大星形胶质细胞中均强烈表达。我们的研究结果强烈表明，在具有不同细胞活性的MS病变中发现的各种TGF-β亚型及其受体类型的表达参与了导致慢性MS病变形成的反应过程。
