A longitudinal study on IL-2, sIL-2R, IL-4 and IFN-gamma in multiple sclerosis CSF and serum.

The cerebrospinal fluid (CSF) and serum levels of interleukin-2 (IL-2), soluble IL-2 receptor (sIL-2R), interleukin-4 (IL-4) and interferon-gamma (IFN-gamma) were longitudinally investigated in 20 multiple sclerosis (MS) patients. There were 80 paired CSF and serum samples (range 2-8 per patient) covering a 1-5 year (mean 2.5 year) period. Increased levels of IL-2 and sIL-2R were found in 56 and 71%, respectively, of MS sera. In all patients, one or several sera (totally 89%) exhibited values above the normal range for either one of the components or both. The occurrence of IL-2 or sIL-2R positive CSF specimens was much lower, 15 and 9%, respectively. Only 3 MS sera (from one patient) had clearly detectable IL-4 and no CSF samples were definitely positive. IFN-gamma was undetectable in all serum and CSF specimens. No correlations were found between the immunological parameters and the clinical disease activity. The cytokine patterns in MS give strong support for the presence of a systemic T-cell activation. Furthermore, the data argue for a predominant activation of an IL-2- and sIL-2R-producing but not IL-4-producing T-helper (Th) lymphocyte subpopulation, Th1/CD4 + CD45R + cells.     

Serum soluble interleukin-2 receptor levels in chronic progressive, stable and steroid-treated multiple sclerosis

Serum levels of the soluble interleukin-2 receptor (sIL-2R), an indicator of T cell activation, were significantly elevated in chronic progressive MS (CPMS) patients, clinically stable MS patients and in patients with other neurological diseases (OND) as compared to healthy controls. Levels of sIL-2R in steroid treated CPMS patients were markedly lower than in untreated CPMS patients and were comparable to healthy controls. Thus, systemic T cell activation occurs in MS during clinically stable and progressive disease stages and in other neurological disorders. The ability of oral corticosteroids to depress serum sIL-2R levels in vivo may be one mechanism by which they exert their therapeutic effect.     

Immune activation in multiple sclerosis: study of IL-2, sIL-2R, and gamma-IFN levels in serum and cerebrospinal fluid

Serum and cerebrospinal fluid (CSF) levels of interleukin-2 (IL-2), soluble IL-2 receptor (sIL-2R), and gamma-interferon (gamma-IFN) were measured in multiple sclerosis (MS) patients, human immunodeficiency virus type 1 (HIV-1)-infected patients and normal controls (NC). Increased levels of both IL-2 and sIL-2R were found in MS serum. Moreover, 11 of 50 MS patients showed detectable levels of IL-2 in the CSF. HIV-1-infected patients had increased levels of sIL-2R in serum and, less frequently, in the CSF. gamma-IFN was never detected in serum and CSF of all the patients studied. These findings confirm preliminary reports, further stress a systemic T-cell activation in MS, and support the hypothesis that an immunologic disorder exists in such patients.     

Interleukin-2, soluble interleukin-2-receptor,neopterin,l-tryptophan and β2-microglobulin levels in CSF and serum of patients with relapsing-remitting or chronic-progressive multiple sclerosis

Cerebrospinal fluid (CSF) and serum levels of interleukin-2 (IL-2), soluble IL-2 receptors (sIL-2R), neopterin,l-tryptophan (l-TRP) and ₂-microglobulin ((₂-M) were measured in 31 untreated multiple sclerosis patients in acute exacerbation and 27 normal controls. Twenty-six patients showed the relapsing-remitting type of disease (RRMS); 5 had a chronic-progressive course (CPMS). No changes in serum IL-2 and sIL-2R were found between RRMS patients and controls, whereas serum and CSF levels as well as the CSF/serum ratio of neopterin were significantly elevated in the RRMS group. IL-2 was not detectable in CSF of patients or controls and sIL-2R levels were at the level of the lower detection (LD) sensitivity of the ELISA method. Four of 23 RRMS patients versus 1 of 25 controls showed CSF sIL-2R levels above the LD sensitivity, indicating a trend towards elevation in acute relapse. No difference was found in serum and CSFl-TRP and ₂-M of patients and controls. In CSF of RRMS patients neopterin andl-TRP correlated negatively, reflecting the interferon-gamma mediated activation of macrophages in acute relapse. A significant positive correlation (Spearman rank 0.57,P = 0.001) between serum IL-2 levels and duration of acute relapse (mean 30 days) warrants further evaluation.     

Evaluation of IL-2, sIL2R, IL-6, TNF-alpha, and IL-1 beta levels in serum and CSF of patients with optic neuritis.

Optic neuritis (ON) is characterized by immune-mediated demyelination of the optic nerve. In this study we addressed the question of cytokine signalling as part of activation of the immune system. 20 patients with first episode of acute idiopathic unilateral ON, prolonged visual evoked potentials, but normal 1.5 tesla MRI of the brain, and normal somatosensory evoked potentials were included into the study. Paired cerebrospinal fluid (CSF) and serum samples of these patients were analyzed for the presence of interleukin (IL-)-2, soluble IL-2R (sIL2R), IL-6, tumor necrosis factor (TNF)-alpha, and IL-1 beta by an enzyme-linked immunosorbent assay (IL-2, sIL2R, TNF-alpha, IL-1 beta) or a bioassay (IL-6). IL-2 was significantly elevated in the CSF (P < 0.01), whereas sIL2R (P < 0.01) and IL-6 (P < 0.01) were significantly increased in serum. TNF-alpha could not be detected in CSF or serum, and IL-1 beta was negative in serum in all but one sample and positive in only low amount (mean 9 pg/ml) in the CSF of 6/20 patients. This cytokine pattern in ON indicates an activation of the immune system within and outside the central nervous system with a predominance of T-cell activation.     

Serum cytokine levels in chronic progressive multiple sclerosis: interleukin-2 levels parallel tumor necrosis factor-alpha levels

Serum levels of the cytokines interleukin-1 alpha (IL-I alpha), IL-1 beta, IL-2, IL-4, IL-6, tumor necrosis factor-alpha (TNF-alpha) and the soluble IL-2 receptor were measured in chronic progressive multiple sclerosis patients (CPMS) and normal, inflammatory, and noninflammatory disease controls. Serum IL-2 levels displayed the most consistent abnormalities in the group of tests for the CPMS group, and were the only cytokine levels to achieve significance in statistical group analyses. However, several patients with CPMS had normal serum IL-2 levels. An incidental finding was a statistical correlation between serum IL-2 and TNF-alpha levels among all groups tested. This finding was supported on analysis of serial serum samples from CPMS patients. These results suggest a linkage of IL-2 and TNF-alpha production, especially in pathological conditions.     

Soluble interleukin-1 receptor type II levels are elevated in cerebrospinal fluid in Alzheimer's disease patients

Evidence from epidemiological, clinical and experimental studies favour the hypothesis that inflammatory events are part of the neuropathology in Alzheimer's disease. Proinflammatory cytokines such as interleukin-1 (IL-1), interleukin-6 (IL-6) and tumour necrosis factor-alpha (TNF-alpha) have been found in activated microglia in the vicinity of amyloid plaques in Alzheimer's disease brain. In the present study, the levels of soluble IL-1 receptor type II (sIL-1R type II), IL-1 receptor antagonist (IL-1ra), IL-1beta, IL-6 and TNF-alpha were analyzed in cerebrospinal fluid (CSF) samples from Alzheimer's disease patients and control subjects. The levels of sIL-1R type II were significantly higher in CSF from Alzheimer's disease patients than in CSF samples from control subjects (38.5+/-8 pg/ml (mean+/-S.E.M.) vs. 7.9+/-4 pg/ml, p<0.05). Measurements of the proinflammatory cytokines IL-6 and TNF-alpha showed no significant difference between the two groups, and the levels of IL-1beta and IL-1ra in the present material were too low to permit detection. The increased levels of sIL-1R type II may reflect a compensatory mechanism to balance an increased release of IL-1 receptor agonists in the Alzheimer's disease brain.     

Tumor necrosis factor-alpha, interleukin-1beta and interleukin-6 in the cerebrospinal fluid of newborn with meningitis

OBJECTIVE: To analyze the usefulness of determining the cerebrospinal fluid (CSF) levels of tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta) and interleukin-6 (IL-6) for the early diagnosis and evaluation of the prognosis of neonatal meningitis. METHOD: We studied 54 newborn that underwent lumbar puncture. Thirty patients had meningitis and 24 were the control group. CSF and sera were obtained at the moment of suspicion of meningitis and stored at -70 degrees C. Cytokines were performed by enzyme-linked immunosorbent assay method. RESULTS: CSF cytokines were detected in all the newborn with meningitis. TNF-alpha was detected in the CSF in 63.3% of the neonates, IL-1beta in 73.3% and IL-6 in 96.6%. The CSF levels were significantly higher than serum in neonates with meningitis. There was no correlation between the CSF levels of cytokines and neurologic complications. CONCLUSION: The detection of TNF-alpha, IL-1beta and IL-6 in the CSF is of great value in order to achieve a early diagnosis of neonatal meningitis. Among the three cytokines analyzed, IL-6 was the best indicator of meningeal inflammation.     

Concentration of interleukin-18, interleukin-1beta, soluble receptor for interleukin-1 (sIL-1RII) and C-reactive protein in patients with neuroborreliosis

BACKGROUND AND PURPOSE: The aim of the present study was to determine the role of interleukin-18 (IL-18), interleukin-1beta (IL-1beta) and its soluble receptor sIL-1RII in the pathogenesis of neuroborreliosis as well as the usefulness of C-reactive protein (CRP) determination in the diagnosis and monitoring of treatment of Lyme neuroborreliosis. MATERIAL AND METHODS: The study group consisted of 20 patients with Lyme meningitis (age range 16-72 years, mean age 42.6 years). For measurements of IL-18, IL-1beta and sIL-1RII levels in serum and cerebrospinal fluid (CSF) the control group consisted of 10 healthy volunteers and 10 patients with infection of the central nervous system ruled out, respectively. Cytokines and sIL-1RII levels in serum and CSF were measured twice, before and after the 30-day treatment period. Serum and CSF levels of IL-18, IL-1beta and sIL-1RII were measured using ELISA, and CRP serum levels were measured using the immunoturbidimetric method. RESULTS: Before the treatment the concentration of IL-18, IL-1beta and sIL-1RII in serum as well as in CSF was significantly higher as compared to the controls. After the treatment end the level of IL-18, IL-1beta and sIL-1RII was reduced but the serum level of sIL-1RII and CSF level of IL-18 and sIL-1RII remained significantly higher than in the control group. The serum level of CRP was increased only in 15% of patients and after the treatment CRP concentration returned to a basal level (except one patient in whom CRP was slightly higher than in the control group). No correlation between CRP and IL-18, IL-1beta and sIL-1RII was observed. CONCLUSIONS: Our results confirm the involvement of IL-18, IL-1beta and sIL-1RII in the pathogenesis of neuroborreliosis and uselessness of CRP determination in the diagnosis of Lyme meningitis.     

Elevated levels of interleukin-12 and interferon-gamma in patients with human T lymphotropic virus type I-associated myelopathy

The levels of interleukin-12 (IL-12) (p70 heterodimer), total IL-12 (p70 heterodimer plus p40 chains), interferon-gamma (IFN-gamma) as Th1 cytokine, and those of interleukin-4 (IL-4) and interleukin-10 (IL-10) as Th2 cytokines in sera and cerebrospinal fluid (CSF) from 22 patients with human T lymphotropic virus type I (HTLV-I)-associated myelopathy (HAM) were compared with those of 22 patients with other neurological diseases (OND), including nine anti-HTLV-I-seropositive carriers. Both serum IL-12 (total and p70 heterodimer) and CSF IFN-gamma, measured by the enzyme-linked immunosorbent assay (ELISA), were significantly elevated in patients with HAM as compared to the patients with OND, including the anti-HTLV-I-seropositive carriers. Serum IFN-gamma also was significantly elevated in the HAM patients as compared to the controls. There was no significant difference in the CSF levels of IL-12 (total and p70 heterodimer) between the HAM patients and controls, whereas, for the Th2 cytokines IL-4 was detected in the CSF of four anti-HTLV-I-seropositive carriers of the 13 control patients but not in any of the patients with HAM. No significant difference was found in the serum levels of IL-4 and IL-10, nor in the CSF levels of IL-10 in the patients with HAM and in the controls. These findings indicate that in patients with HAM, the immunological balance of helper T lymphocytes between Th1 and Th2 is toward Th1 in the periphery and that Th1-mediated immunological status in the central nervous system is involved in the pathogenesis of HAM.     

Comparative analysis of cytokine patterns in immunological, infectious, and oncological neurological disorders

Interleukins (IL) 1, 2, 4, 6 and soluble IL-2 receptor (sIL-2R), interferon-gamma (IFN-gamma), and tumor necrosis factor-alpha (TNF-alpha) were measured in CSF and serum from patients with relapsing-remitting and chronic multiple sclerosis, Guillain-Barré syndrome, chronic inflammatory demyelinating polyradiculoneuropathy, HIV infection, bacterial meningitis, viral encephalitis, meningeal carcinomatosis, hematologic meningeal malignancies, and disseminated melanoma. Our findings suggest that monitoring of disease activity in neuroimmunologic disorders by means of IL-1 beta, IL-2, sIL-2R, or IL-4 determination will not prove useful. IL-6, on the other hand, indicates relapse in multiple sclerosis and active disease in Guillain-Barré syndrome and meningeal carcinomatosis. High CSF TNF-alpha in metastatic melanoma and frequent detection in CSF of the multifunctional B-cell growth factor, IL-6 (27/30) and oligoclonal immunoglobulin bands (33%) in meningeal carcinomatosis confirm an intrathecal immune response in disseminated leptomeningeal neoplasia which might be amenable to therapeutic immunomodulation.     

Clinical correlation with serum-soluble interleukin-2 receptor levels in Guillain-Barré syndrome

In patients with Guillain-Barré syndrome (GBS) soluble interleukin-2 receptor (sIL-2R) levels were elevated compared with those of patients with other neurologic diseases (OND), and of healthy controls. Smaller increases in sIL-2R levels occurred in OND patients compared to healthy subjects. Monitoring of GBS patients clearly demonstrated that decreases in sIL-2R levels correlated with clinical recovery. Thus, T-cell activation may be relevant in the pathogenesis of GBS.     

In vivo relationship of interleukin-2 and soluble IL-2 receptor to blood-brain barrier impairment in patients with active multiple sclerosis

Interleukin (IL)-2 has well-recognized effects on cerebral endothelial cells and, therefore, may mediate disruption of the blood-brain barrier in patients with multiple sclerosis (MS). To evaluate the in vivo relationship of the IL-2 system to blood-brain barrier impairment in MS, levels of IL-2 and soluble IL-2 receptors (sIL-2R) in cerebrospinal fluid (CSF) and serum samples from 50 patients with active MS and 49 controls were correlated with values of the CSF to serum albumin ratio. Intrathecal levels of IL-2 and sIL-2R were significantly higher in MS compared with the control groups and correlated with albumin ratios in MS patients. Intrathecal levels of IL-2 and sIL-2R also correlated with the degree of barrier damage in these patients. It is suggested that intrathecal levels of IL-2 and sIL-2R are related to barrier impairment in MS and may be important in understanding some of the pathological changes of this condition.     

Cerebrospinal fluid cytokines in AIDS dementia complex

Summary We evaluated cerebrospinal fluid (CSF) and serum concentrations of interleukin-1-alpha (IL-1 alpha), interleukin-6 (IL-6) and tumour necrosis factor alpha (TNF-alpha) in 30 patients with AIDS dementia complex (ADC), and in 20 HIV-seronegative subjects with other neurological diseases (OND). CSF TNF alpha, IL-1-alpha and IL-6 were more frequently detectable in ADC patients than in OND subjects. These cytokines were also detectable in CSF of ADC patients with minimal symptoms. In contrast, the majority of both ADC and OND patients did not contain detectable serum levels of cytokines. Our data support the notion of intrathecal synthesis of cytokines in ADC patients and raise the possibility that activated macrophages may play a significant role in the pathogenesis of ADC.     

Elevated serum levels of interleukin-12 in chronic progressive multiple sclerosis

The serum levels of the heterodimeric cytokine IL-12 were measured by solid-phase ELISA in a group of healthy subjects, multiple sclerosis (MS) patients with secondary chronic progressive course of the disease and patients suffering from other neurological diseases (OND). Serum levels of IL-12 higher than 5 pg/ml (limit of sensitivity of the assay) were only found in 2/30 (6.7%) of the healthy subjects and none of the 8 subjects with OND. In contrast, IL-12 was found in the majority of CPMS patients' sera (10/15, 66.7%) with values ranging between 5.5 and 18.6 pg/ml. These results are suggestive for an up-regulated production of IL-12 in CPMS.     

Neuroleptic treatment increases soluble IL-2 receptors and decreases soluble IL-6 receptors in schizophrenia

The cytokines interleukin-2 (IL-2) and interleukin-6 (IL-6) increase during immune activation, they are released from activated astrocytes and microglial cells in the central nervous system (CNS), and they are able to enhance the catecholaminergic neurotransmission. This study focused on the soluble receptors of IL-2 and IL-6 (sIL-2R, sIL-6R) as a part of the regulation system of IL-2 and IL-6. We studied serum levels of sIL-2R in 30 schizophrenic patients not under neuroleptic medication during an acute exacerbation of the disease and reexamined these patients under neuroleptic treatment after clinical improvement. The SIL-6R levels of 39 schizophrenic patients were estimated under the same conditions. The results were compared with the levels of sIL-2R and sIL-6R in 42 healthy controls. No difference was found between the schizophrenic patients before neuroleptic treatment and the healthy controls. During neuroleptic treatment, however, there was a significant increase of sIL-2R levels and a significant decrease of the sIL-6R levels between the pre- and post-conditions. In comparison with healthy controls, the treatment group also showed increased sIL-2R levels and decreased sIL-6R levels. These results suggest that treatment with neuroleptics is associated with increased sIL-2R and decreased sIL-6R. Since sIL-2R bind and inactivate IL-2, whereas sIL-6R form an active complex with IL-6, the increase of sIL-2R and the decrease of sIL-6R together may reflect a functional down regulation of these activating cytokines. This suggests that neuroleptic therapy has a differentiated immunomodulatory effect.     

Elevated serum interleukin-6 (IL-6) and IL-6 receptor concentrations in posttraumatic stress disorder following accidental man-made traumatic events.

BACKGROUND: Recently, it has been reported that serum interleukin-1 beta (IL-1 beta), but not soluble IL-2 receptor (sIL-2R), concentrations were significantly higher in patients with posttraumatic stress disorder (PTSD) than in normal volunteers, and that psychological stress in humans is associated with increased secretion of proinflammatory cytokines, such as IL-6. METHODS: The aim of the present study was to examine the inflammatory response system in patients with PTSD through measurements of serum IL-6, sIL-6R, sgp130 (the IL-6 signal transducing protein), sIL-1R antagonist (sIL-1RA; an endogenous IL-1 receptor antagonist), CC16 (an endogenous anticytokine), and sCD8 (the T suppressor-cytotoxic antigen). RESULTS: Serum IL-6 and sIL-6R, but not sgp130, sIL-RA, CC16, or sCD8, concentrations were significantly higher in PTSD patients than in normal volunteers. Serum sIL-6R concentrations were significantly higher in PTSD patients with concurrent major depression than in PTSD patients without major depression and normal volunteers. There were no significant relationships between serum IL-6 or sIL-6R and severity measures of PTSD. CONCLUSIONS: The results suggest that PTSD is associated with increased IL-6 signaling. It is hypothesized that stress-induced secretion of proinflammatory cytokines is involved in the catecholaminergic modulation of anxiety reactions.     

Th1 shift in CIDP versus Th2 shift in vasculitic neuropathy in CSF

To investigate the intra- and extracellular levels of various cytokines and chemokines in CSF in chronic inflammatory demyelinating polyneuropathy (CIDP) and vasculitic neuropathy (VN), 16 cytokines, IL-1beta, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12 (p70), IL-13, IL-17, IFN-gamma, TNF-alpha, G-CSF, MCP-1 and MIP-1beta, were measured in CSF supernatant by a multiplexed fluorescent bead-based immunoassay and intracellular production of IFN-gamma and IL-4 in CSF CD4+ T cells were simultaneously measured by flow cytometry in 14 patients with CIDP, 8 patients with VN and 25 patients with other noninflammatory neurologic diseases (OND). In the CSF supernatant, a significant increase of IL-17, IL-8 and IL-6, and a significant decrease of IL-4, IL-5 and IL-7 levels were detected in pretreated CIDP as compared with OND. A significant increase of IL-6, IL-8 and IL-10 levels was found in pretreated VN. Both IL-17 and IL-8 levels correlated strongly with CSF protein levels in CIDP, although the correlation of IL-6 levels was weak. In CSF CD4+ T cells, IFN-gamma+ IL-4- cell percentages were markedly elevated in CIDP compared with OND, but not in VN, resulting in a significant increase of intracellular IFN-gamma/IL-4 ratio in CIDP, even in the absence of CSF pleocytosis. The nonresponders to intravenous immunoglobulins (IVIGs) showed a significantly lower IFN-gamma- IL-4+ CD4+ T cell percentage, and tended to have a higher intracellular IFN-gamma/IL-4 ratio than the responders in CSF. Marked upregulation of Th1 cytokine, IL-17, and downregulation of Th2 cytokines, together with infiltration of IFN-gamma-producing CD4+ T cells are useful markers for CIDP, while several Th2 cytokines are upregulated in VN in CSF.     

IL-1beta, IL-6 and TNF-alpha and outcomes of neonatal hypoxic ischemic encephalopathy

The role of cytokines in the pathogenesis of brain injury and their relation to neurological outcomes of asphyxiated neonates is not fully defined. We hypothesize that interleukin-1 beta (IL-1beta), interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) in cerebrospinal fluid (CSF) correlate with the severity of brain injury and can predict neurological deficits in infants who suffered from hypoxic ischemic encephalopathy (HIE). A prospective study was conducted on 24 term infants diagnosed with HIE and 13 controls. HIE was clinically classified into mild, moderate and severe according to Sarnat and Sarnat grading. Blood and CSF samples were obtained from all infants in the first 24h of life as part of routine investigations for suspected meningitis and/or sepsis. Neurological examination and Denver Developmental Screening Test II (DDST II) were performed at 6 and 12 months of life. IL-1beta, IL-6 and TNF-alpha were all significantly increased in HIE infants when compared to control. IL-1beta in the CSF correlated with the severity of HIE (r=0.61, P=0.001) more than IL-6 (r=0.45, P=0.004) or TNF-alpha (r=0.47, P=0.003). IL-1beta exhibited the highest CSF/serum ratio among the three studied cytokines suggesting its local release in the brain after the initial hypoxic injury. Abnormal neurological findings and/or abnormal DDST II at 6 and 12 months were best predicted by IL-1beta in the CSF (sensitivity=88% and specificity=80%). This study confirms the role of IL-1beta in the ongoing neuronal injury that occurs in the latent phase following the original HIE insult.