Single pancreatic B cells are purified by autofluorescence-activated cell sorting, and their secretory activity is measured after overnight culture. Compared to intact islets, the isolated cells release 2-fold more insulin under basal conditions and 5-fold less during nutrient stimulation. Their secretory activity can be induced by glucose, leucine, or arginine, but only 0.3-1.7% of their hormone content is liberated at 20 mM nutrient concentrations. This poor nutrient-induced insulin release from purified B cells is attributed to their low cAMP levels and is markedly increased after addition of (Bu)2cAMP, of glucagon, or of pancreatic A cells. These results strongly support the concept that the potent in vivo insulin-releasing action of glucose and leucine is not only dependent on their fuel capacity in pancreatic B cells but also on the concurrent cAMP levels in these cells. In isolated islets, endogenously released glucagon apparently determines the cAMP production in B cells and thus participates in the nutrient-induced secretory process. Somatostatin and epinephrine were shown to exert their suppressive effects via the glucagon-dependent messenger system. It is concluded that nutrients and hormones interact with two different messenger systems which amplify each others' stimulatory effect upon insulin release. cAMP might represent the hormone-induced messenger which sets the B cell's sensitivity and secretory capacity for nutrient stimuli such as glucose. The higher insulin secretory response observed after reaggregation of single B cells could not be attributed to an altered activity in the nutrient or hormonal regulatory units, raising the possibility that the aggregated state of the cells is rather responsible for a better organization or cooperation of the secretory effector unit.
The expression of interleukin (IL)-1 beta, IL-6 and their respective receptors has been studied in the rat brain before and up to 24 h after injury. Messenger RNA transcripts of these four genes were detected by in situ hybridization (ISH) in different structures of the intact brain. The distribution was very similar for IL-1 beta, IL-6 and IL-6 receptor (IL-6R). The expression of IL-1R was more widespread. Within hours after injury, an increased expression of IL-1 beta, and thereafter of IL-6 was documented. The expression of IL-1R and IL-6R was also increased. This expression was bilateral and not restricted to the injured area. Within 24 h, all ISH patterns had returned to normal. The molecular data were confirmed by protein data. Indeed, the distribution of IL-6 (detected by immunocytochemistry) agreed with the ISH patterns for IL-6. Furthermore, extracellular fluid was collected by microdialysis at the site of the lesion during 12 h and successive fractions were assayed for the presence of bioactive IL-1 and IL-6. Increases in IL-1 and later in IL-6 levels were detected. The rapid and concomitant increased expression of IL-1 beta, IL-6 and their receptors after injury stresses their possible early role in inflammatory mechanisms also in the brain, before any recruitment of inflammatory cells from remote nervous and not nervous areas.
We report here the role of one of the less studied members of the family of suppressors of cytokine signaling (SOCS), namely SOCS-7, in cytokine signaling. We demonstrate that SOCS-7 inhibits prolactin (PRL), growth hormone (GH), or leptin (LEP) signaling mediated through STAT3 and STAT5 in a dose-dependent manner. SOCS-7 also attenuated STAT3 and STAT5 signaling induced by overexpression of JH1, the catalytic subdomain of JAK2. Since SOCS-7 interacted with phosphorylated STAT3 or STAT5, we assumed that SOCS-7 acts at the level of STAT proteins. Indeed, we showed that SOCS-7 inhibits PRL-and leptin-induced STAT5 and STAT3 phosphorylation and prevented the nuclear translocation of activated STAT3. Taken together, our results indicate that SOCS-7 is a physiological dysregulator of PRL, leptin, and probably also GH signaling and that its mode of action is a novel variation of SOCS protein inhibition of cytokine-inducible STAT-mediated signal transduction.One of the main pathways for the termination of cytokineactivated JAK 1 /STAT signaling is mediated by a family of proteins discovered nearly a decade ago, the suppressors of cytokine signaling (SOCS) (1-4). These proteins' modulatory activity is not restricted to the JAK/STAT pathway; it has also been reported for activities mediated by receptor tyrosine kinases, such as c-Kit and insulin receptor substrate (IRS)-1 to -4 (5-7). The current paradigm attributes the main function of SOCS to the targeting of the affected proteins for ubiquitination and subsequent degradation by the proteasome, although additional mechanisms are also involved (4 -6). The SOCS family consists of eight proteins, termed SOCS-1 through -7 and CIS (cytokineinducible SH2 protein). Whereas CIS and SOCS-1 through -3 have been studied extensively, others, in particular SOCS-7, have been given much less attention. The latter protein was first discovered by Matuoka et al. (8), who cloned its partial cDNA sequence and called it NAP-4 due to its ability to interact with the adaptor proteins Nck, Grb2 (Ash), and Phospholipase C-␥-1. More recently, full sequences of mouse, rat, and human SOCS-7 have been reported (GenBank TM NM_138657 for mouse; XP_213443 for rat; and see Ref. 9 for human). The NAP-4 sequence lacks the 127 N-terminal amino acids of SOCS-7 but has an additional segment of 34 amino acids (exon 4). SOCS-7 is constitutively expressed in several tissues, most strongly in the testis and brain (8, 10, 11), and its expression in leukocytes is stimulated by prolactin (PRL), growth hormone (GH), and interleukin-6 (10). Recently, SOCS-7 (and SOCS-6) has been shown to interact with IRS-2 and IRS-4 (11). However, to date, no report concerning the possible biological role of SOCS-7 has been published aside from our recent work showing that SOCS-7 interacts with the cytoskeleton proteins actin and vinexin and is present in cell membranes (9). This latter finding prompted us to study whether SOCS-7 affects biological activities mediated through the membrane-embedded receptors of three cytokines: GH ...
Chronic frontal lobe functional deficits after traumatic brain injury (TBI) may be associated with altered catecholamine systems in the frontal cortex. To test this, tyrosine hydroxylase (TH) and dopamine beta-hydroxylase (DBH) levels were examined by immunohistochemistry and Western blot at 1, 7, 14, and 28 days after TBI or sham surgery. No alterations in DBH levels were observed by Western blot at any time point examined, but there was a significant increase in TH expression 28 days after TBI (optical density 334 +/- 68% or 3.3-fold, ipsilateral and 218 +/- 39% or 2.2-fold, contralateral) relative to the sham controls. The increase in TH may reflect a compensatory response of dopaminergic neurons to upregulate their synthesizing capacity and increase the efficiency of dopamine neurotransmission chronically after TBI.
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