transforming-growth-factor-beta and Central-Nervous-System-Diseases

Neurotrophic factors (NTFs) play an important role in maintaining homeostasis of the central nervous system (CNS) by regulating the survival, differentiation, maturation, and development of neurons and by participating in the regeneration of damaged tissues. Disturbances in the level and functioning of NTFs can lead to many diseases of the nervous system, including degenerative diseases, mental diseases, and neurodevelopmental disorders. Each CNS disease is characterized by a unique pathomechanism, however, the involvement of certain processes in its etiology is common, such as neuroinflammation, dysregulation of NTFs levels, or mitochondrial dysfunction. It has been shown that NTFs can control the activation of glial cells by directing them toward a neuroprotective and anti-inflammatory phenotype and activating signaling pathways responsible for neuronal survival. In this review, our goal is to outline the current state of knowledge about the processes affected by NTFs, the crosstalk between NTFs, mitochondria, and the nervous and immune systems, leading to the inhibition of neuroinflammation and oxidative stress, and thus the inhibition of the development and progression of CNS disorders.

Topics: Brain Diseases; Central Nervous System Diseases; Humans; Nerve Growth Factors; Neuroglia; Neuroinflammatory Diseases; Neurons; Transforming Growth Factor beta

The pleiotropic cytokine transforming growth factor-beta 1 (TGFβ1) plays pivotal roles in different cell types, including immune cells such as T cells, monocytes/macrophages, and microglia. Microglia are essential during physiological and pathological events. Maturation of postnatal microglia, as well as the regulation of the complex functional repertoire of microglia, needs to be carefully orchestrated. However, an understanding of how mammalian microglia maturation and disease-associated microglia activation is regulated remains fragmentary. Here, we summarize recent observations made by employing transgenic approaches to silence microglial TGFβ signaling in mice. These revealed that TGFβ1 and TGFβ signaling are indispensable for microglia maturation, adult microglia homeostasis, and the control of microglia activation in central nervous system pathologies.

Topics: Animals; Central Nervous System Diseases; Homeostasis; Humans; Microglia; Signal Transduction; Transforming Growth Factor beta

Bacterial and viral infections have long been implicated in pathogenesis and progression of multiple sclerosis (MS). Incidence and severity of its animal model experimental autoimmune encephalomyelitis (EAE) can be enhanced by concomitant administration of pertussis toxin (PTx), the major virulence factor of Bordetella pertussis. Its adjuvant effect at the time of immunization with myelin antigen is attributed to an unspecific activation and facilitated migration of immune cells across the blood brain barrier into the central nervous system (CNS). In order to evaluate whether recurring exposure to bacterial antigen may have a differential effect on development of CNS autoimmunity, we repetitively administered PTx prior to immunization. Mice weekly injected with PTx were largely protected from subsequent EAE induction which was reflected by a decreased proliferation and pro-inflammatory differentiation of myelin-reactive T cells. Splenocytes isolated from EAE-resistant mice predominantly produced IL-10 upon re-stimulation with PTx, while non-specific immune responses were unchanged. Longitudinal analyses revealed that repetitive exposure of mice to PTx gradually elevated serum levels for TGF-β and IL-10 which was associated with an expansion of peripheral CD4(+)CD25(+)FoxP3(+) regulatory T cells (Treg). Increased frequency of Treg persisted upon immunization and thereafter. Collectively, these data suggest a scenario in which repetitive PTx treatment protects mice from development of CNS autoimmune disease through upregulation of regulatory cytokines and expansion of CD4(+)CD25(+)FoxP3(+) Treg. Besides its therapeutic implication, this finding suggests that encounter of the immune system with microbial products may not only be part of CNS autoimmune disease pathogenesis but also of its regulation.

Topics: Animals; Autoimmune Diseases; CD4-Positive T-Lymphocytes; Cell Proliferation; Central Nervous System Diseases; Female; Forkhead Transcription Factors; Interleukin-10; Interleukin-2 Receptor alpha Subunit; Mice; Mice, Inbred C57BL; Pertussis Toxin; T-Lymphocytes; T-Lymphocytes, Regulatory; Transforming Growth Factor beta

We investigated cerebrospinal fluid (CSF) samples from patients with Creutzfeldt-Jakob disease (CJD) and other neurological diseases. Concentrations of pro- and anti-inflammatory cytokines IL-1beta, IL-6, IL-8, IL-12, TNF-alpha and TGF-beta 2 were determined in CSF using ELISA. Significant changes were found for IL-8 and TGF-beta 2. IL-8 levels were elevated in the CSF of CJD patients. Of interest, the increase was significant to other dementia and to controls. In contrast, TGF-beta 2 was significantly decreased in CSF of CJD compared to all groups. IL-1beta, IL-12 and TNF-alpha could not be detected in CSF or in case of IL-6 in only low concentrations without significant difference.

Topics: Adolescent; Adult; Aged; Central Nervous System Diseases; Creutzfeldt-Jakob Syndrome; Dementia; Enzyme-Linked Immunosorbent Assay; Epilepsy; Female; Humans; Inflammation; Interleukin-8; Male; Middle Aged; Sensitivity and Specificity; Statistics, Nonparametric; Transforming Growth Factor beta

Topics: Central Nervous System Diseases; Humans; Immunity, Cellular; Mycobacterium tuberculosis; Transforming Growth Factor beta; Tuberculosis; Tumor Necrosis Factor-alpha

We have previously shown that the brains of patients with Alzheimer's disease (AD) express transforming growth factor (TGF)-beta 2 in neurofibrillary tangle (NFT)-bearing neurons and reactive astrocytes. The present study was undertaken to determine whether other neurodegenerative diseases were also associated with an alteration of the TGF-beta's. The immunohistochemical expression of TGF-beta 1, -2 and -3 was assessed in the brains of patients with progressive supranuclear palsy (n = 2), amyotrophic lateral sclerosis (n = 3), Lewy body disease (n = 5), Parkinson's disease (n = 1), Shy-Drager syndrome (n = 1), Pick's disease (n = 3), lobar atrophy (n = 1), and corticobasal degeneration (n = 2). Our results were compared to norms for controls (n = 8). We found expression of TGF-beta 2 in both NFT bearing neurons and tangle-bearing glial cells in progressive supranuclear palsy and in neurons with age-related NFT formation. Widespread staining of reactive astrocytes for TGF-beta 2 was observed in all degenerative diseases. TGF-beta 1 and -3 staining was not selectively altered in these diseases. We conclude that induction of TGF-beta 2 may be an intrinsic part of the processes that underlie NFT formation and reactive gliosis in a variety of neurodegenerative diseases.

Topics: Adult; Aged; Aged, 80 and over; Case-Control Studies; Central Nervous System Diseases; Female; Humans; Male; Middle Aged; Nerve Degeneration; Neuroglia; Neurons; Transforming Growth Factor beta

Topics: Adult; Animals; Central Nervous System Diseases; Clinical Trials as Topic; Growth Substances; Humans; Tibial Fractures; Transforming Growth Factor beta; Wound Healing