M. Hurme

Plasma levels of interleukin-1β and interleukin-6 in schizophrenia, other psychoses, and affective disorders

Plasma levels of interleukin (IL)-1 beta and IL-6 were measured in 60 acutely hospitalized psychiatric patients and in 60 healthy controls by enzyme-linked immunosorbent assay (ELISA). Almost no IL-6 was detected in the plasma of the patients or controls. The mean level of IL-1 beta was found to be significantly higher in schizophrenic patients than in their corresponding controls (P = 0.03). The acute schizophrenics, but not the group of chronic schizophrenics, contributed to this increase. No correlation with age, duration of illness or overt psychopathology was found. The neuroleptic medication did not prove to have a significant effect on the plasma IL-1 beta levels. There was no difference between non-psychotic affective disorder patients (N = 17) and the controls.

Modulation ofinterleukin-1β production by cyclic AMP in human monocytes

Elevation of cAMP has been considered to be an important downregulative signal in the production ofinterieukin‐1(IL‐1). This study demonstrates that this phenomenon is dependent on the signal used to activate the IL‐1 production. The IL‐1β production of lipopolysaccharide activated human monocytes was readily inhibited by dibutyryl cAMP. This took place without a significant change in the steady‐state levels of IL‐1β mRNA. By contrast, in PMA activated monocytes 100 μM dibutyryl cAMP increased in IL‐1β production ca. 4‐fold. The steady‐statelevels of IL‐1β mRNA were also simultaneously increased.

Plasma and Cerebrospinal Fluid lnterleukin-1 β and lnterleukin-6 in Hospitalized Schizophrenic Patients

Interleukin (IL)-1β and IL·6 levels in plasma and cerebrospinal fluid (CSF) of 14 medicated schizophrenic patients and 9 controls were measured by enzyme-linked immunosorbent assay. Almost no detectab

FGF21 is a biomarker for mitochondrial translation and mtDNA maintenance disorders

Objective: To validate new mitochondrial myopathy serum biomarkers for diagnostic use. Methods: We analyzed serum FGF21 (S-FGF21) and GDF15 from patients with (1) mitochondrial diseases and (2) nonmitochondrial disorders partially overlapping with mitochondrial disorder phenotypes. We (3) did a meta-analysis of S-FGF21 in mitochondrial disease and (4) analyzed S-Fgf21 and skeletal muscle Fgf21 expression in 6 mouse models with different muscle-manifesting mitochondrial dysfunctions. Results: We report that S-FGF21 consistently increases in primary mitochondrial myopathy, especially in patients with mitochondrial translation defects or mitochondrial DNA (mtDNA) deletions (675 and 347 pg/mL, respectively; controls: 66 pg/mL, p < 0.0001 for both). This is corroborated in mice (mtDNA deletions 1,163 vs 379 pg/mL, p < 0.0001). However, patients and mice with structural respiratory chain subunit or assembly factor defects showed low induction (human 335 pg/mL, p < 0.05; mice 335 pg/mL, not significant). Overall specificities of FGF21 and GDF15 to find patients with mitochondrial myopathy were 89.3% vs 86.4%, and sensitivities 67.3% and 76.0%, respectively. However, GDF15 was increased also in a wide range of nonmitochondrial conditions. Conclusions: S-FGF21 is a specific biomarker for muscle-manifesting defects of mitochondrial translation, including mitochondrial transfer-RNA mutations and primary and secondary mtDNA deletions, the most common causes of mitochondrial disease. However, normal S-FGF21 does not exclude structural respiratory chain complex or assembly factor defects, important to acknowledge in diagnostics. Classification of evidence: This study provides Class III evidence that elevated S-FGF21 accurately distinguishes patients with mitochondrial myopathies from patients with other conditions, and FGF21 and GDF15 mitochondrial myopathy from other myopathies.

High expression of the Thy-1 antigen on natural killer cells recently derived from bone marrow

The subset of murine natural killer (NK) cells that kills lymphoma targets contains about 50% cells expressing the Thy-1 antigen and this has been one of the reasons for assigning NK cells to the T-cell differentiation lineage. It has now been shown that the proportion of the Thy-1+ NK cells is not constant: ca. 90% of the NK cells appearing in the spleens of irradiated mice injected 10-14 days previously with bone marrow cells (anti-Thy-1 plus complement treated) express this antigen. The donor origin of these Thy-1+ NK cells was demonstrated by using semisyngeneic bone marrow cells in transfers but this same phenomenon could also be observed after entirely syngeneic transfers, excluding the possibilities that this Thy-1+ NK activity is due to activated T cells or to the effect of T-cell activation products on NK cells. Additionally, these early NK cells expressed the asialo-GM1 antigen, which is found on murine NK cells but not on cytotoxic T cells. These data suggest that the precursors for NK cells in the bone marrow are Thy-1-, and that the first splenic NK cells derived from these progenitors express this antigen.

Activation of NF-κB by cAMP in human myeloid cells

Nuclear factor kappa B (NF‐κB) is a DNA‐binding regulatory factor that controls the transcription of a number of genes. Various agents are known to activate this factor. We have studied the ability of cAMP to stimulate NF‐κB activity in human myeloid cells. Electrophoretic mobility assay revealed that structural cAMP analogs and agents elevating intracellular cAMP levels induced NF‐κB DNA‐binding activity. The inducibility was dependent on the maturation stage of myeloid cells. In promyelocytic HL‐60 cells cAMP induced higher NF‐κB activity than in more differential THP‐1 cells and in human monocytes. By transfecting HL‐60 and THP‐1 cells with reporter constructs containing NF‐κB DNA‐binding sites, we observed that cAMP‐induced NF‐κB was transcriptionally active.

Cytotoxic T-cell responses to H-Y:Ir genes and associative antigens map inH-2

The secondary cytotoxic responses to the male-specific antigen (H-Y) in mice showH-2 restriction so that the cytotoxic female cell must share the K- and/or D-end antigen with the male target cells. The association with the K and/or D end varies with differentH-2 haplotypes,e.g., H-2b cytotoxic cells require the H-2Db antigen(s) on the target cells, while cytotoxic cells fromH-2b/H-2d F1 mice sensitized toH-2d male cells kill only male targets having H-2Kd antigen(s). This association of H-Y with appropriate K/D antigens seems to be needed also in the induction of the cytotoxic response. Of the independent haplotypes, onlyH-2b strains are capable of making secondary anti-H-Y responses and this trait seems to be dominant,i.e., the F1 strains with oneH-2b parent are able to produce anti-H-Y cytotoxic cells against both theH-2b parent and the nonresponder parent. The mating of the two nonresponder strains may produce F1 mice which are responders, thus suggestingIr gene complementation. Mapping data indicates that at least one of these complementary genes is located in theI-C region fork/s complementation.

Signal transduction pathways leading to the production of IL-8 by human monocytes are differentially regulated by dexamethasone.

Previous studies have shown that IL‐8 gene expression is enhanced by various stimuli, which induce different signal transduction pathways. A lipopolysaccharide (LPS)‐induced pathway has been reported to be inhibited by glucocorticoids in monocytes. We have now examined the effect of dexamethasone on the LPS‐induced and other signal transduction pathways leading to the production of IL‐8 by human monocytes. Dexamethasone Inhibited the production of IL‐8 stimulated with a cyclic adenosine monophosphate analog or LPS. In contrast, dexamethasone had no significant effect on a phorbol ester (PMA)‐stimulated IL‐8 production. These results suggest that the signal transduction pathways leading to the production of IL‐8 by human monocytes are differentially regulated by dexamethasone.

Regulation of interleukin-1β production by glucocorticoids in human monocytes: the mechanism of action depends on the activation signal

Glucocorticoids are known to downregulate interleukin-1 beta production in monocytic cells by two different mechanims: direct inhibition of the gene transcription and destabilization of the preformed interleukin-1 beta mRNA. Now we have examined the effect of the nature of the monocyte activating signal on these two inhibitory mechanims. When human monocytes were preincubated with dexamethasone for 1 hour and then stimulated either with bacterial lipopolysaccharide or phorbol myristate, it was found that dexamethasone inhibited the lipopolysaccharide-induced interleukin-1 beta protein production, but the phorbol myristate-induced production was increased 3-10 fold. This difference was also seen at the mRNA level. When dexamethasone was added to the cultures 3 hours after the stimulators, it clearly decreased the interleukin-1 beta mRNA levels regardless of the stimulator used (although the effect was clearly weaker on the PMA-induced mRNA). Thus these data suggest that the phorbol myristate-induced signal (prolonged protein kinase C activation?) cannot be inhibited by prior incubation with dexamethasone and it also protects the induced mRNA for the degradative action of dexamethasone.

Regulation of endothelial adhesion molecules by ligands binding to the scavenger receptor

Monocyte adherence to the endothelium, their penetration to the subendothelial space and excessive lipid accumulation (foam cell formation) are the initial events in atherogenesis. Scavenger receptors have been reported to play an important role in foam cell formation, since modified low density lipoproteins can be taken up via scavenger receptors in a non‐down‐regulated fashion. In this study we demonstrate that stimulation of scavenger receptors in endothelial cells induces the expression of endothelial adhesion molecules. Polyinosinic acid (poly I), a known scavenger receptor ligand, significantly induced the expression of intercellular adhesion molecule‐1 (ICAM‐1), vascular cell adhesion molecule‐1 (VCAM‐1) and E‐selectin on human umbilical vein endothelial cells when compared with polycytidylic acid (poly C), a structurally related compound to poly I, which does not bind to the scavenger receptor. The effect of scavenger receptor ligands on the endothelial cell line EA hy. 926 was also tested. Poly I up‐regutated ICAM‐1 expression also on EA hy. 926 cells, whikit had no effect on IL‐lβ or tumour necrosis factor‐alpha (TNF‐α) production on the same cell line. Poly I‐induced ICAM‐1 expression on EA hy. 926 cells could be inhibited by H7, a protein kinase C inhibitor, while HA 1004, a preferential protein kinase A inhibitor, had no effect on ICAM‐1 expression. The role of protein kinase C in scavenger receptor‐mediated adhesion molecule up‐regulation was confirmed by the ability of poly I to directly activate protein kinase C, when measured with 3H‐phorbol dibutyrate binding to EA hy. 926 cells, while poly C again was ineffective.