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At least 757 records · Page 42Linked to original sources
PubMed2000

G13alpha-mediated PYK2 activation. PYK2 is a mediator of G13alpha -induced serum response element-dependent transcription.

G(12)alpha/G(13)alpha transduces signals from G-protein-coupled receptors to stimulate growth-promoting pathways and the early response gene c-fos. Within the c-fos promoter lies a key regulatory site, the serum response element (SRE). Here we show a critical role for the tyrosine kinase PYK2 in muscarinic receptor type 1 and G(12)alpha/G(13)alpha signaling to an SRE reporter gene. A kinase-inactivate form of PYK2 (PYK2 KD) inhibits muscarinic receptor type 1 signaling to the SRE and PYK2 itself triggers SRE reporter gene activation through a RhoA-dependent pathway. Placing PYK2 downstream of G-protein activation but upstream of RhoA, the expression of PYK2 KD blocks the activation of an SRE reporter gene by GTPase-deficient forms of G(12)alpha or G(13)alpha but not by RhoA. The GTPase-deficient form of G(13)alpha triggers PYK2 kinase activity and PYK2 tyrosine phosphorylation, and co-expression of the RGS domain of p115 RhoGEF inhibits both responses. Finally, we show that in vivo G(13)alpha, although not G(12)alpha, readily associates with PYK2. Thus, G-protein-coupled receptors via G(13)alpha activation can use PYK2 to link to SRE-dependent gene expression.

Amino Acid Substitution↗
PubMed1973

The mediator of cellular immunity. VI. Effect of the antimitotic drug vinblastine on the mediator of cellular resistance to infection.

The antimitotic drug vinblastine (Vbl) has a profound impact upon the specifically sensitized lymphocytes that transfer cellular resistance to Listeria monocytogenes. A 12-h pulse of the drug given to prospective donors during the first week of an immunizing Listeria infection inhibits the delivery of protective lymphocytes to the thoracic duct and their subsequent movement into an inflammatory exudate induced in the peritoneal cavity. The effect of Vbl is clearly related to its antimitotic activity, not to an effect on lymphocytes regardless of their position in the division cycle. This conclusion was drawn from an autoradiographic analysis of cells in the lymph of Vbl-treated rats and from failure of the drug to abrogate a known function of small lymphocytes, namely, their ability to initiate a graft-vs.-host reaction. The results imply that large lymphocytes, the rapidly proliferating cells in central lymph, are the principal effector cells responsible for transmitting resistance to L. monocytogenes and provide a plausible explanation for their rapid turnover and short circulating life-span.

Animals↗
PubMed1999

A role for neutral sphingomyelinase-mediated ceramide production in T cell receptor-induced apoptosis and mitogen-activated protein kinase-mediated signal transduction.

Studying apoptosis induced by T cell receptor (TCR) cross-linking in the T cell hybridoma, 3DO, we found both neutral sphingomyelinase activation and production of ceramide upon receptor engagement. Pharmacological inhibition of ceramide production by the fungal toxin, fumonisin B1, impaired TCR-induced interleukin (IL)-2 production and programmed cell death. Addition of either exogenous ceramide or bacterial sphingomyelinase reconstituted both responses. Moreover, specific inactivation of neutral sphingomyelinase by antisense RNA inhibited IL-2 production and mitogen-activated protein kinase activation after TCR triggering. These results suggest that ceramide production by activation of neutral sphingomyelinase is an essential component of the TCR signaling machinery.

Animals↗
PubMed2001

Differential regulation of T cell receptor-mediated Th1 cell IFN-gamma production and proliferation by divergent cAMP-mediated redox pathways.

Culture of an H-2(s)-restricted, bovine myelin basic protein (BMBP)-specific murine Th1 clone with the adenyl cyclase agonist forskolin (FSK) or isobutylmethylxanthine (IBMX), an inhibitor of cAMP catabolism, before culture with anti-CD3 or BMBP and antigen-presenting cells (APC) suppressed antigen or anti-CD3-induced proliferation and production of interferon-gamma (IFN-gamma). Other H-2(s)-derived or H-2(b)-derived clones specific for BMBP or keyhole limpet hemocyanin (KLH) were similarly affected. FSK did not affect the expression of CD4 or the T cell receptor (TCR) but did diminish levels of the phosphorylated (activated) mitogen-activated protein (MAP) kinases early response kinase-1 (ERK-1) and ERK-2. Immunoblotting of lysates from an FSK-treated Th1 clone with antibodies to a carboxy-terminal epitope of p56(lck), a signal transduction enzyme upstream from ERK-1 and ERK2, did not detect p56(lck) unless the lysates were reduced prior to electrophoresis. Immunoblotting of nonreduced lysates with antibodies to an amino-terminal epitope demonstrated p56(lck) with a lower apparent molecular weight, characteristic of oxidized proteins. Reduction restored the detection of p56(lck) by anticarboxy-terminal p56(lck) and to mobilities indistinguishable from controls detected by the antiamino-terminal p56(lck). N-acetylcysteine or catalase prevented FSK-induced suppression of antigen-induced proliferation and the loss of carboxy-terminal epitopes of p56(lck). An inhibitor of cAMP-dependent protein kinase A (PKA) or nitric oxide synthase (NOS) did not affect FSK-induced inhibition of antigen-induced proliferation. In contrast, inhibitors of PKA or NOS, but not catalase, prevented FSK-induced suppression of IFN-gamma production. Moreover, immunoblots of lysates precipitated with anti-p56(lck), phosphotyrosine, or CD4 demonstrated that in FSK-treated, anti-CD3-stimulated cells, p56(lck) is not associated with CD4 zeta chain, nor is p56(lck) or zeta chain phosphorylated. In vitro kinase assays demonstrated that p56(lck) from FSK-treated cells does not have kinase activity. Taken together, the results suggest that an elevation of intracellular cAMP (in the absence of antigen) creates an oxidative environment that oxidizes and inactivates p56(lck) by an H(2)O(2)-dependent, PKA-independent mechanism and inhibits the production of IFN-gamma by an NO, PKA-dependent mechanism. Thus, antigen-induced proliferation and IFN-gamma production in a Th1 clone are controlled separately by different cAMP-dependent, redox-based mechanisms.

1-Methyl-3-isobutylxanthine↗
PubMed1988

Direct comparison of electric field-mediated and PEG-mediated cell fusion for the generation of antibody producing hybridomas.

As an alternative to polyethylene glycol (PEG), electric field pulses offer, in theory, fusion conditions whose parameters are better controllable. In 1985 (1) we reported on the successful generation of hybridoma clones by means of electrofusion performed in a batch-type manner similar to that usually employed with PEG, and applicable to any type of antigens. Here we summarize the results of a series of fusions performed since then in which both electric field and PEG induced fusion were directly compared. Different types of antigens were used. Electrofusion resulted in a 3.8 to 33.0 times higher yield of hybridomas per unit number of spleen cells. Moreover, hybridomas grew more vigorously after fusion and, therefore, were earlier visible. Other parameters examined revealed no differences between hybridomas generated by either method.

Animals↗
PubMed1998

Hypothalamic-pituitary-mediated immunomodulation: arginine vasopressin is a neuroendocrine immune mediator.

Organisms respond to a variety of environmental agents, such as those that cause inflammation, by mounting a coordinated complex series of adaptive responses involving the immune, nervous and endocrine systems. These adaptations are aimed at restoring the homeostatic balance and the return to the status quo ante. This interaction is facilitated by cytokines, hormones and neurotransmitters, as well as receptors that are endogenous to the neural, immune and endocrine systems. These shared ligands and receptors provide the molecular basis of this cross-talk. Studies of animal models of autoimmune diseases have shown that defects in the neuroendocrine immune communications contribute to the development of chronic inflammatory autoimmune disease. By analogy, similar observations have now been made in patients with inflammatory rheumatic disorders. For instance, patients with rheumatoid arthritis have abnormally low cortisol responses to inflammation, whilst the production of prolactin is excessive and dysregulated. Prolactin is a pro-inflammatory neuropeptide. This paper reviews the evidence to support the viewpoint that the neuropeptide arginine vasopressin, which is also produced by the hypothalamus, should be considered to be another neuroendocrine modulator of immune and inflammatory responses. It is also being hypothesized that the production of arginine vasopressin might be dysregulated and excessive in rheumatoid arthritis, and that this could be another additional neuroendocrine factor contributing to the pathophysiology of the disease.

Animals↗
PubMed1993

Functional study on the effects of nifedipine, cromakalim, and the absence of extracellular Ca2+ on alpha 1-adrenoceptor-mediated excitation-contraction coupling in isolated rat portal vein: comparison with depolarization-mediated excitation-contraction coupling.

The effects of Ca(2+)-entry blockade by nifedipine, K+ channel opening by cromakalim, and of omitting extracellular Ca2+ on the contractile response elicited by a supramaximum concentration of the "full" and selective alpha 1-adrenoceptor agonist phenylephrine (10(-4) M) were compared with those elicited by a supramaximal concentration of KCl (50 mM) in isolated rat portal vein. The contractile response to phenylephrine appeared to be biphasically composed of an early "transient" phase and a slowly developing "sustained" phase that reached maximum values after 30 s and 5 min after initiation of contraction, respectively. The contractile response to KCl (50 mM) exhibited a triphasic pattern consisting of "spike," "transient", and "sustained" components that peaked after 8 s, 25 s, and 10 min, respectively. Nifedipine was able to eliminate all components of the contractions in response to both phenylephrine and KCl almost completely. Nifedipine was approximately 10 times more potent at suppressing the slowly developing sustained components of the contractions in response to both stimuli than the early transient components. The spontaneous myogenic contractions were inhibited by nifedipine with intermediate potency. Cromakalim, in contrast to nifedipine, selectively eliminated the early transient components of the contractions in response to both phenylephrine and KCl. The sustained components of the contractions in response to both stimuli were relatively resistant to K+ channel opening, although higher concentrations (> 1 microM) of cromakalim were capable of antagonizing the sustained response to phenylephrine accompanied by oscillations in tone. Cromakalim was most potent in counteracting spontaneous myogenic contractions. When phenylephrine and KCl were added with or without external Ca2+ after different periods of equilibration in nominally Ca(2+)-free medium, different washout kinetics for the different components of the contractions in response to both stimuli were observed. The early transient phases of tension development in response to both stimuli were completely lost after approximately 6 min of equilibration in nominally Ca(2+)-free medium, whereas the slowly developing sustained components of the contractions were immediately lost after the change to nominally Ca(2+)-free medium. Externally added Ca2+, when administered together with phenylephrine or KCl after the preparations had been exposed for different times to nominally Ca(2+)-free medium, could not restore the early transient components.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed2000

Secreted products of a nonmucoid Pseudomonas aeruginosa strain induce two modes of macrophage killing: external-ATP-dependent, P2Z-receptor-mediated necrosis and ATP-independent, caspase-mediated apoptosis.

A nonmucoid clinical isolate of Pseudomonas aeruginosa, strain 808, elaborated ATP-dependent and ATP-independent types of cytotoxic factors in the growth medium. These cytotoxic factors, active against macrophages, were secreted during the exponential phase of growth in a complex medium. Commensurate with the appearance of the cytotoxic activities in the cell-free growth medium, several ATP-utilizing enzymic activities, such as adenylate kinase, nucleoside diphosphate kinase and 5'-nucleotidase (ATPase and/or phosphatase), were detected in the medium. These ATP-utilizing enzymes are believed to convert external ATP, presumably effluxed from macrophages, to various adenine nucleotides, which then activate purinergic receptors such as P2Z, leading to enhanced macrophage cell death. Pretreatment of macrophages with periodate-oxidized ATP (oATP), which is an irreversible inhibitor of P2Z receptor activation, prevented subsequent ATP-induced macrophage cell death. A second type of cytotoxic factor(s) operated in an ATP-independent manner such that it triggered activation of apoptotic processes in macrophages, leading to proteolytic conversion of procaspase-3 to active caspase-3. This cytotoxic factor(s) did not appear to act on procaspase-3 present in macrophage cytosolic extracts. Intact macrophages, when exposed to the cytotoxic factor(s) for 6-16 h, underwent apoptosis and demonstrated the presence of active caspase-3 in their cytosolic extracts. Interestingly, two redox proteins, azurin and cytochrome c(551), were detected in the cytotoxic preparation. When cell-line-derived or peritoneal macrophages or mast cells were incubated overnight with Q-Sepharose column flow-through fraction or with a mixture of azurin and cytochrome c(551), they underwent extensive cell death due to induction of apoptosis.

Adenosine Triphosphate↗
PubMed2002

OSM1/SYP61: a syntaxin protein in Arabidopsis controls abscisic acid-mediated and non-abscisic acid-mediated responses to abiotic stress.

To identify the genetic loci that control salt tolerance in higher plants, a large-scale screen was conducted with a bialaphos marker-based T-DNA insertional collection of Arabidopsis ecotype C24 mutants. One line, osm1 (for osmotic stress-sensitive mutant), exhibited increased sensitivity to both ionic (NaCl) and nonionic (mannitol) osmotic stress in a root-bending assay. The osm1 mutant displayed a more branched root pattern with or without stress and was hypersensitive to inhibition by Na(+), K(+), and Li(+) but not Cs(+). Plants of the osm1 mutant also were more prone to wilting when grown with limited soil moisture compared with wild-type plants. The stomata of osm1 plants were insensitive to both ABA-induced closing and inhibition of opening compared with wild-type plants. The T-DNA insertion appeared in the first exon of an open reading frame on chromosome 1 (F3M18.7, which is the same as AtSYP61). This insertion mutation cosegregated closely with the osm1 phenotype and was the only functional T-DNA in the mutant genome. Expression of the OSM1 gene was disrupted in mutant plants, and abnormal transcripts accumulated. Gene complementation with the native gene from the wild-type genome completely restored the mutant phenotype to the wild type. Analysis of the deduced amino acid sequence of the affected gene revealed that OSM1 is related most closely to mammalian syntaxins 6 and 10, which are members of the SNARE superfamily of proteins required for vesicular/target membrane fusions. Expression of the OSM1 promoter::beta-glucuronidase gene in transformants indicated that OSM1 is expressed in all tissues except hypocotyls and young leaves and is hyperexpressed in epidermal guard cells. Together, our results demonstrate important roles of OSM1/SYP61 in osmotic stress tolerance and in the ABA regulation of stomatal responses.

Abscisic Acid↗
PubMed2005

HYPERSENSITIVE TO RED AND BLUE 1, a ZZ-type zinc finger protein, regulates phytochrome B-mediated red and cryptochrome-mediated blue light responses.

Plant photoreceptors that regulate photomorphogenic development include red/far-red-light-absorbing phytochromes and blue/UV-A-light-absorbing cryptochromes. We have undertaken a genetic screen to identify additional components downstream of the photoreceptors in Arabidopsis thaliana. We identified a short hypocotyl mutant under red and blue light, hypersensitive to red and blue 1 (hrb1). Mutation in HRB1 also enhances the end-of-day far-red light response, inhibits leaf expansion and petiole elongation, and attenuates the expression of CAB3 and CHS. Double mutant analysis indicates that phyB is epistatic to hrb1 under red light, and cry1 cry2 is epistatic to hrb1 under blue light for both hypocotyl growth and light-regulated gene expression responses. HRB1 localizes to the nucleus and belongs to a protein family of Drought induced 19 (Di19). HRB1 and all other family members contain a ZZ-type zinc finger domain, which in other organisms is implicated in protein-protein interactions between dystrophin and calmodulin and between transcriptional adaptors and activators. HRB1 activity is also required for red and blue light-induced expression of PHYTOCHROME INTERACTING FACTOR 4 (PIF4). pif4 shows a very similar hypersensitive response as hrb1 to both red light and blue light and is epistatic to hrb1 in control of light-regulated gene expression responses. Thus, the roles of HRB1 and PIF4 together in regulating both red and blue light responses may represent points where red light signaling and blue light signaling intersect.

Amino Acid Sequence↗
PubMed2004

Sleep deprivation impairs hippocampus-mediated contextual learning but not amygdala-mediated cued learning in rats.

Prolonged sleep deprivation results in cognitive deficits. In rats, for example, sleep deprivation impairs spatial learning and hippocampal long-term potentiation. We tested the effects of sleep deprivation on learning in a Pavlovian fear conditioning paradigm, choosing a sleep deprivation paradigm in which REM sleep was completely prevented and non-REM sleep was strongly decreased. During conditioning, rats were given footshocks, either alone or paired with a tone, and tested 24 h later for freezing responses to the conditioning context, and to the tone in a novel environment. Whereas control animals had robust contextual learning in both background and foreground contextual conditioning paradigms, 72 h of sleep deprivation before conditioning dramatically impaired both types of contextual learning (by more than 50%) without affecting cued learning. Increasing the number of footshocks did not overcome the sleep deprivation-induced deficit. The results provide behavioural evidence that REM/non-REM sleep deprivation has neuroanatomically selective actions, differentially interfering with the neural systems underlying contextual learning (i.e. the hippocampus) and cued learning (i.e. the amygdala), and support the involvement of the hippocampus in both foreground and background contextual conditioning.

Amygdala↗
PubMed2005

Estren-mediated inhibition of T lymphopoiesis is estrogen receptor-independent whereas its suppression of T cell-mediated inflammation is estrogen receptor-dependent.

Estrogen has extensive effects on the immune system. The aim of the present experiments was to compare the effects of 17beta-estradiol (E2) and 4-estren-3alpha,17beta-diol (estren) on T lymphopoiesis and T cell-dependent inflammation. In order to investigate the role of estrogen receptors (ER) in the effects of E2 and estren on the immune system, ER knock-out mice lacking both ERalpha and ERbeta (DERKO) were used. T lymphopoiesis and T cell-dependent inflammation were studied by investigating thymus cellularity, the delayed-type hypersensitivity (DTH) reaction, CD4(+) T cells in spleen and serum levels of interleukin (IL)-6. As expected, the presence of ERs was mandatory for all the effects of E2. In contrast, treatment with estren reduced thymus cellularity in ER knock-out mice, indicating an effect through ER-independent pathways. Interestingly, estren suppressed only DTH, the frequency of CD4(+) T cells in spleen and serum levels of IL-6 in wild-type (WT) mice, but not in mice lacking ERs. Thus, our study is the first to show that estren inhibits T lymphopoiesis via ER-independent pathways, whereas its suppressive effects on inflammation are ER-dependent.

Animals↗
PubMed1983

Sendai-virus-induced cell-mediated cytotoxicity in vitro. The role of viral glycoproteins in cell-mediated cytotoxicity.

Treatment of peripheral blood lymphocytes from normal donors with small amounts of purified Sendai virions results in enhanced cellular cytotoxicity in vitro to uninfected tissue culture target cells (virus-dependent cellular cytotoxicity (VDCC)), without any obvious correlation to the natural cytotoxicity (NK) displayed by the lymphocytes in the absence of virus. Removal from the virions of the two surface components present in the viral envelope, the HN glycoprotein (gp 71), carrying haemagglutinating and neuraminidase activity, and the F glycoprotein (gp 49), carrying fusion activity, by treatment with pronase abrogated their capacity to induce VDCC. Similar results were obtained when virions lacking the HN glycoprotein after treatment with chymotrypsin were added to the lymphocytes. In contrast, treatment of the virus particles with trypsin, which removed the F glycoprotein, did not affect their capacity to induce VDCC. When the solubilized and separated peplomers were used for lymphocyte treatment, either alone or in combination, the purified HN glycoprotein had full capacity to induce VDCC, whereas the F glycoprotein was inactive. These results suggest that the HM peplomer is solely or primarily responsible for the cytolytic activity arising in non-sensitized lymphocytes when confronted with certain viruses.

Adult↗