Cardiac hypertrophy is a well known response to increased hemodynamic load. Mechanical stress is considered to be the trigger inducing a growth response in the overloaded myocardium. Furthermore, mechanical stress induces the release of growth-promoting factors, such as angiotensin II, endothelin-1, and transforming growth factor-beta, which provide a second line of growth induction. In this review, we will focus on the primary effects of mechanical stress: how mechanical stress may be sensed, and which signal transduction pathways may couple mechanical stress to modulation of gene expression, and to increased protein synthesis. Mechanical stress may be coupled to intracellular signals that are responsible for the hypertrophic response via integrins and the cytoskeleton or via sarcolemmal proteins, such as phospholipases, ion channels and ion exchangers. The signal transduction pathways that may be involved belong to two groups: (1) the mitogen-activated protein kinases (MAPK) pathway; and (2) the janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway. The MAPK pathway can be subdivided into the extracellular-regulated kinase (ERK), the c-Jun N-terminal kinase (JNK), and the 38-kDa MAPK (p38 MAPK) pathway. Alternatively, the stress signal may be directly submitted to the nucleus via the cytoskeleton without the involvement of signal transduction pathways. Finally, by promoting an increase in intracellular Ca2+ concentration stretch may stimulate the calcium/calmodulin-dependent phosphatase calcineurin, a novel hypertrophic signalling pathway.

Objective: To study the effects of the active metabolite of vitamin D 3 , 1,25(OH) 2 D 3 , an immunomodulatory hormone, on the generation of so-called immature dendritic cells (iDCs) generated from monocytes (Mo-iDCs). Design and methods: Human peripheral blood monocytes were cultured to iDCs in the presence of granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin (IL)-4 for 1 week, with or without the extra addition of 10 28 M 1,25(OH) 2 D 3 to the culture. Their phenotypes (CD14, CD1a, CD83, HLA-DR, CD80, CD86 and CD40 expression) were examined by¯uorescence-activated cell sorting, and their T-cell stimulatory potential was investigated in allogeneic mixed lymphocyte reaction (allo-MLR). Additionally, their in vitro production of IL-10, IL-12 and transforming growth factor b (TGF-b) were examined by using the enzyme-linked immunosorbent assay. Results: When 1,25(OH) 2 D 3 was added to monocytes in culture with GM-CSF and IL-4, it hampered the maturation of Mo-iDCs. First, the phenotype of the 1,25(OH) 2 D 3 -differentiated DCs was affected, there being impaired downregulation of the monocytic marker CD14 and impaired upregulation of the markers CD1a, CD83, HLA-DR, CD80 and CD40. CD86 was expressed on more 1,25(OH) 2 D 3 -differentiated DCs. Secondly, the T-cell stimulatory capability of 1,25(OH) 2 D 3 -differentiated DCs was upregulated relative to the original monocytes to a lesser degree than DCs differentiated without 1,25(OH) 2 D 3 when tested in an allo-MLR. With regard to the production of cytokines, Staphylococcus aureus cowan 1 strain (SAC)-induced IL-10 production, although not enhanced, remained high in 1,25(OH) 2 D 3 -differentiated DCs, but was strongly downregulated in DCs generated in the absence of 1,25(OH) 2 D 3 . SAC/interferon-g-induced IL-12 production was clearly upregulated in both types of DC relative to those of the original monocytes, and TGF-b production was downregulated. Conclusion: Our data con®rm earlier reports showing that 1,25(OH) 2 D 3 hampers the maturation of fully active immunostimulatory major histocompatibility complex (MHC) class II+, CD1a+, CD80+ DCs from monocytes. Our data supplement the data from other reports by showing that the expression of CD86 was upregulated in 1,25(OH) 2 D 3 -differentiated DCs, whilst the capacity for IL-10 production remained high. Collectively, these data are in line with earlier descriptions of suppressive activities of this steroid-like hormone with respect to the stimulation of cell-mediated immunity.

Blood monocytes have an altered proinflammatory status in BD. Lithium treatment restores this altered status. Short-term in vitro exposure of monocytes to lithium has other effects than lithium treatment.

OBJECTIVE— There is evidence that monocytes of patients with type 1 diabetes show proinflammatory activation and disturbed migration/adhesion, but the evidence is inconsistent. Our hypothesis is that monocytes are distinctly activated/disturbed in different subforms of autoimmune diabetes. RESEARCH DESIGN AND METHODS— We studied patterns of inflammatory gene expression in monocytes of patients with type 1 diabetes (juvenile onset, n = 30; adult onset, n = 30) and latent autoimmune diabetes of the adult (LADA) ( n = 30) (controls subjects, n = 49; type 2 diabetic patients, n = 30) using quantitative PCR. We tested 25 selected genes: 12 genes detected in a prestudy via whole-genome analyses plus an additional 13 genes identified as part of a monocyte inflammatory signature previously reported. RESULTS— We identified two distinct monocyte gene expression clusters in autoimmune diabetes. One cluster (comprising 12 proinflammatory cytokine/compound genes with a putative key gene PDE4B ) was detected in 60% of LADA and 28% of adult-onset type 1 diabetic patients but in only 10% of juvenile-onset type 1 diabetic patients. A second cluster (comprising 10 chemotaxis, adhesion, motility, and metabolism genes) was detected in 43% of juvenile-onset type 1 diabetic and 33% of LADA patients but in only 9% of adult-onset type 1 diabetic patients. CONCLUSIONS— Subgroups of type 1 diabetic patients show an abnormal monocyte gene expression with two profiles, supporting a concept of heterogeneity in the pathogenesis of autoimmune diabetes only partly overlapping with the presently known diagnostic categories.

In the epidermis, the keratinocytes are the first cells to be encountered by external stimuli and they are able to promote the inflammatory response by increased production and release of various cytokines. In their turn, these cytokines may directly affect the production of proinflammatory cytokines in human dermal fibroblasts. In addition, in both epithelial and mesenchymal cells cytokine production may be modu lated by their mutual interaction, and thereby regulate the inflammatory response. The present study aimed to examine the role of fibroblasts in the regulation of proinflammatory IL-1, IL-6 and IL-8 levels induced by keratinocyte-derived IL-1. The data show that in fibroblasts exposed to conditioned media derived from cultures of normal human keratinocytes or squamous carcinoma cells (SCC-4), both the IL-8 and IL-6 mRNA expression as well as protein production were elevated. In addition, it was shown that these effects subsequent internalization and intracellular degrada tion is the most likely mechanism involved in the re duction of IL-1 levels by fibroblasts. Comparing the rate of IL-1 reduction in the presence of various cell types indicated that the rate of IL-1 reduction is di rectly related to the number of IL-1 receptors found on these cell types. In conclusion, these results indicate that the release of IL -la by activated keratinocytes may act as an inducer of IL-8 and IL-6 production in neighbouring fibroblasts. This may be an important pathway for the amplification of the inflammatory re sponse. The amounts of both cytokines produced by fi broblasts were at least two to three orders of magni tude higher than those produced by keratinocytes, suggesting an important role of fibroblasts in the gen eral inflammatory response. Furthermore, fibroblasts might be involved in turning off this inflammatory re sponse by reducing IL-1 levels, most likely via IL-1 rewere induced by IL -la . The IL -la-induced increase in ceptor-mediated uptake. IL-8 and IL-6 production, both on the protein level as well as on the mRNA level, were concentration depen dent and occurred almost simultaneously. W hile the induction of IL-6 and IL-8 occurred simultaneously, the IL-6 mRNA remained elevated for longer. In con-------------------trast to increased IL-6 and IL-8 production the I L -la IntroductionKey words Interleukin-8 ■ Interleukin-1 ♦ IL-l receptor ratinoeyte -Fibroblast interaction levels markedly decreased upon culturing o f fibro blasts in keratinocyte-derived conditioned medium. rr h e r e is increasing evidence that the release and producFrom internalization experiments it could be con-tion of cytokines, either preformed o.r newly synthesized, eluded that binding of IL-1 to IL-1 receptors, and its by keratinocytes and fibroblasts is altered after certain events, such as skin injury [I], The keratinocytes become 'activated1 and release, amongst other things, the proin flammatory cytokine interleukin-1 (IL-1) |2 |. It has been shown that exposure of skin cells to IL-l leads to an in creased production...

No abstract

Thyroid autoimmune diseases are complex, polygenic afflictions the penetrance of which is heavily dependent on various environmental influences. In their pathogenesis, an afferent stage (enhanced autoantigen presentation), a central stage (excessive expansion and maturation of autoreactive T and B cells), and an efferent stage (effects of autoreactive T cells and B cells on their targets) can be discerned. At each stage, a plethora of inborn, endogenous or exogenous factors is able to elicit the abnormalities characteristic of that stage, thus opening the gateway to thyroid autoimmunity. Iodine is an important exogenous modulating factor of the process. In general, iodine deficiency attenuates, while iodine excess accelerates autoimmune thyroiditis in autoimmune prone individuals. In nonautoimmune prone individuals, the effects of iodine are different. Here iodine deficiency precipitates a mild (physiological) form of thyroid autoimmune reactivity. Iodine excess stimulates thymus development. Iodine probably exerts these effects via interference in the various stages of the autoimmune process. In the afferent and efferent stage, iodine-induced alterations in thyrocyte metabolism and even necrosis most likely play a role. By contrast, in the central phase, iodine has direct effects on thymus development, the development and function of various immune cells (T cells, B cells macrophages and dendritic cells) and the antigenicity of thyroglobulin.

The circadian distribution of motor activity and immobility of 14 unmedicated narcoleptics and matched controls was evaluated by monitoring continuous wrist motor activity 5 successive days and nights at home. Sleep was also assessed by sleep logs. The amplitude of the circadian rhythm of motor activity and immobility was significantly lower in narcoleptics than in controls. The variables that best distinguish narcoleptics from controls were the diurnal and nocturnal mean duration of uninterrupted immobility, which can be explained by excessive daytime sleepiness and frequent nocturnal awakenings, respectively. Thus, measures of diurnal and nocturnal motor activity and immobility appear useful for the objective assessment of some of the sleep-wakefulness manifestations of narcolepsy.