The alterations of cerebrospinal fluid TNF-alpha and TGF-beta2 levels in early relapsing-remitting multiple sclerosis.

AIM OF THE STUDY: This study aimed to analyze serum and cerebrospinal fluid (CSF) concentrations of proinflammatory and anti-inflammatory cytokines produced by T regulatory (Treg) cells in early RRMS according to the 2017 McDonald criteria. CLINICAL RATIONALE FOR THE STUDY: Multiple sclerosis (MS) is a chronic, inflammatory, demyelinating disease of the central nervous system (CNS) with the cytokine network playing an important role. However, there is a continual lack of data regarding the immunopathogenesis of early RRMS, especially according to the 2017 McDonald criteria. MATERIALS AND METHODS: The study groups included early RRMS patients during relapse (n = 18), remission (n = 14), and the control group. The MS diagnosis was established according to the 2017 McDonald criteria. Patients were studied up to 1 year after diagnosis was made. A quantitative test kit based on ELISA was used for cytokine measurement in the serum and CSF. Comparative and correlation analyses between the levels of TNF-α, TGF-ß2, IgG index, and relapse duration were performed. RESULTS: Significantly higher CSF concentrations of TNF-α in both RRMS-relapse and RRMS-remission groups were found compared to the controls (p < 0.01). The CSF levels of TGF-ß2 in the RRMS-relapse group were significantly lower in comparison to the control group (p = 0.01). CONCLUSIONS AND CLINICAL IMPLICATIONS: An inappropriate inflammatory response seems to occur in early RRMS and includes the production of TNF-α and a decrease in TGF-ß2 release suggesting a significant Treg cells role. Further studies on the topic may contribute to developing new disease-modifying drugs and biochemical markers of the disorder.

TGF beta1 and TGF beta2 and their role in posthemorrhagic hydrocephalus following SAH and IVH.

OBJECTIVE: Posthemorrhagic hydrocephalus (pHC) is a serious complication following subarachnoid hemorrhage (SAH) and intraventricular hemorrhage (IVH). Besides known clinical predictors, different cytokines have drawn attention to the development of chronic hydrocephalus. Transforming growth factor (TGF) ß1 and TGF ß2 are involved in fibrogenesis, scar formation, cell survival, and tissue differentiation and may play a role in the occurrence of pHC. TGF ß1 is stored in platelets in large amount and is released in the cerebrospinal fluid (CSF) after SAH and IVH. Both TGF ß1 and TGF ß2 can be expressed by various intracranial cells. METHODS: TGF ß1 and ß2 were measured in CSF and blood samples of 42 patients with SAH or IVH with acute hydrocephalus during the first 10 days after ictus. Furthermore, albumin was measured in CSF as an indicator for the amount of blood. Patients were categorized as developing pHC requiring shunt treatment or not-developing pHC within 6 months. RESULTS: After adjusting for age, SAH resulted significantly more often in pHC than did IVH. Plasma levels of TGF ß1 showed a marked increase over time, whereas CSF levels of TGF ß1 constantly decreased. The time course of TGF ß1 and albumin in CSF was paralleled and did not correlate with the development of shunt dependent pHC. Also, TGF ß1 plasma concentrations did not correlate with shunt dependent pHC. TGF ß2 concentrations in plasma showed stable values over time without any variations. TGF ß2 in CSF described a parabolic course with a peak at day 6 after ictus. No correlation was found concerning TGF ß2 in plasma or CSF and shunt dependent pHC. CONCLUSION: TGF ß1 in CSF is derived by platelets from the cisternal or ventricular clot. TGF ß2 in CSF is derived as a general reaction of traumatized brain tissue. These data do not confirm a crucial role of TGF ß1 and TGF ß2 release in the development of pHC.

Transforming growth factor-beta inhibits the expression of clock genes.

Disturbances of sleep-wake rhythms are an important problem in Alzheimer's disease (AD). Circadian rhythms are regulated by clock genes. Transforming growth factor-beta (TGF-ß) is overexpressed in neurons in AD and is the only cytokine that is increased in cerebrospinal fluid (CSF). Our data show that TGF-ß2 inhibits the expression of the clock genes Period (Per)1, Per2, and Rev-erbα, and of the clock-controlled genes D-site albumin promoter binding protein (Dbp) and thyrotroph embryonic factor (Tef). However, our results showed that TGF-ß2 did not alter the expression of brain and muscle Arnt-like protein-1 (Bmal1). The concentrations of TGF-ß2 in the CSF of 2 of 16 AD patients and of 1 of 7 patients with mild cognitive impairment were in the dose range required to suppress the expression of clock genes. TGF-ß2-induced dysregulation of clock genes may alter neuronal pathways, which may be causally related to abnormal sleep-wake rhythms in AD patients.

High CSF transforming growth factor beta levels after subarachnoid haemorrhage: association with chronic communicating hydrocephalus.

BACKGROUND: Chronic communicating hydrocephalus is a common sequela of subarachnoid haemorrhage and develops when the flow and drainage of CSF are impaired after fibrosis in the subarachnoid space. Released by platelets into the CSF after subarachnoid haemorrhage, transforming growth factor (TGF)beta1/beta2 are potent fibrogenic agents that may promote post-haemorrhagic fibrosis and chronic communicating hydrocephalus. METHODS: Temporal changes in total (latent plus active) TGFbeta1/beta2 CSF levels of post-haemorrhage patients developing acute hydrocephalus were measured using ELISA to discover if titres were higher in patients that subsequently developed chronic communicating hydrocephalus, compared with those that did not. RESULTS: Mean (SD) CSF levels of total TGFbeta1 were 97 (42) pg/ml and total TGFbeta2 were 395 (39) pg/ml in control patients with (non-haemorrhagic) hydrocephalus. For days 1-5 post-subarachnoid haemorrhage (dph), levels of 1427 (242) pg/ml and 976 (191) pg/ml were seen for total TGFbeta1 and TGFbeta2, respectively. Beyond 5 dph, total TGFbeta1/beta2 levels declined but remained significantly elevated (p<0.01) above control patient values for at least 19 dph. Haemorrhagic patients that went on to develop chronic communicating hydrocephalus had significantly higher levels of total TGFbeta1 (p<0.01) and TGFbeta2 (p<0.05) between 1 and 9 dph, compared with those of haemorrhagic patients that did not. CONCLUSIONS: Acutely measured levels of TGFbeta1/beta2 in the CSF of patients with subarachnoid haemorrhage are thus potential prognostic biomarkers for the subsequent development of chronic communicating hydrocephalus, indicating likely dependency on CSF shunting.

Decreased levels of interleukin-10 and transforming growth factor-beta 2 in cerebrospinal fluid of patients with high grade astrocytoma.

OBJECTIVE: Glioma cells can produce anti-inflammatory cytokines such as interleukin-10 (IL-10) and transforming growth factor-beta (TGF-beta) which inhibit T cell and monocyte function. It is unknown if production of these cytokines is limited to the site of tumor or these molecules are also released to cerebrospinal fluid and blood. The goal of our study was to determine if patients with astrocytoma have increased levels of IL-10 and TGF-beta 2 in cerebrospinal fluid (CSF) and serum. METHODS: CSF and serum samples were taken from 16 patients with astrocytoma of grade III or grade IV according to the WHO classification and from 28 age- and gender-matched controls (patients with normal pressure hydrocephalus or with lumbar disk herniation). Cytokine concentrations were measured using ELISA methods. RESULTS AND DISCUSSION: There was no difference in serum levels of IL-10 and TGF-beta 2 between groups. Patients with astrocytoma had decreased levels of IL-10 (0.9 +/- 1.2 versus 3.5 +/- 9.2 pg/ml, p=0.01) and TGF-beta 2 (0.0 +/- 0.0 versus 5.4 +/- 9.4 pg/ml, p=0.05) in CSF compared to controls. Because serum IL-10 and TGF-beta 2 levels are similar in patients with astrocytoma and in controls, these cytokines are probably not directly involved in peripheral monocyte and T cell deactivation.