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1.
Trends Immunol ; 22(6): 308-11, 2001 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-11377289

RESUMO

Studies have indicated that purified soluble polysaccharide antigens can elicit T cell-independent Ig responses in vivo, although these responses can be modulated by T cells in a noncognate manner. Relatively little is known, however, concerning the parameters that regulate polysaccharide-specific, as well as protein-specific, Ig isotype responses to an intact extracellular bacterium. Using the murine in vivo humoral response to intact Streptococcus pneumoniae as a model it can be shown that CD4+ T-cell receptor alphabeta+ T cells deliver help for both polysaccharide- and protein-specific Ig responses. However, these responses differ fundamentally in their mechanism of action.


Assuntos
Formação de Anticorpos , Infecções Pneumocócicas/imunologia , Streptococcus pneumoniae/imunologia , Subpopulações de Linfócitos T/imunologia , Animais , Linfócitos T CD4-Positivos/imunologia , Células Dendríticas/imunologia , Células Dendríticas/microbiologia , Isotipos de Imunoglobulinas/imunologia , Modelos Imunológicos , Receptores de Antígenos de Linfócitos T alfa-beta/imunologia
2.
Int Immunol ; 12(8): 1167-72, 2000 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-10917891

RESUMO

The enhancer complex located 3' to the C(H)alpha gene in the IgH locus (3alphaE) may regulate B cell function through its ability to act as a locus control region. Multiple, functionally relevant NF-kappaB binding sites are located within the 3'alphaE. NF-kappaB subunits, especially p50 and c-Rel, have also been shown to play critical and differential roles in regulating B cell proliferation, Ig secretion, germline C(H) transcription and Ig class switching. Thus, NF-kappaB could regulate B cell function in part through modulation of 3'alphaE activity. In this study we determined whether p50 and/or c-Rel regulate 3'alphaE activity in normal murine B cells and whether this depends on the nature of the B cell activator. For this purpose, we crossed p50- and c-Rel-deficient mice with mice that are transgenic for a 3'alphaE-hsl,2-human beta-globin reporter gene, and established p50(-/-) or c-Rel(-/-) mice homozygous for the enhancer transgene. We show, using optimal stimulating conditions, that p50 selectively augments 3'alpha E-hsl,2 activity in lipopolysaccharide-activated B cells, whereas c-Rel is required for optimal 3'alphaE-hs1,2 induction in B cells activated through CD40.


Assuntos
Linfócitos B/metabolismo , Elementos Facilitadores Genéticos , Genes de Imunoglobulinas , Cadeias Pesadas de Imunoglobulinas/genética , Ativação Linfocitária/fisiologia , NF-kappa B/fisiologia , Proteínas Proto-Oncogênicas c-rel/fisiologia , Animais , Linfócitos B/efeitos dos fármacos , Linfócitos B/imunologia , Sítios de Ligação , Antígenos CD40/fisiologia , Ligante de CD40/fisiologia , Cruzamentos Genéticos , Dexametasona/farmacologia , Dimerização , Genes Reporter , Globinas/biossíntese , Globinas/genética , Interleucina-4/farmacologia , Lipopolissacarídeos/farmacologia , Ativação Linfocitária/efeitos dos fármacos , Ativação Linfocitária/genética , Camundongos , Camundongos Knockout , Camundongos Transgênicos , NF-kappa B/química , NF-kappa B/genética , Subunidade p50 de NF-kappa B , Proteínas Proto-Oncogênicas c-rel/química , Proteínas Proto-Oncogênicas c-rel/genética , Proteínas Recombinantes de Fusão/fisiologia
3.
J Immunol ; 162(4): 1941-6, 1999 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-9973462

RESUMO

B cells lacking individual NF-kappa B/Rel family members exhibit defects in activation programs. We generated small resting B cells lacking p65 or p50 alone, or lacking both p50 and p65, then evaluated the ability of these cells to proliferate, secrete Ig, and undergo Ig class switching. B cells lacking p65 proliferated well in response to all stimuli tested. However, these cells demonstrated an isolated defect in switching to IgG3, which was associated with a decrease in gamma 3 germline CH gene expression. Whereas, previously reported, B cells lacking p50 alone had a severe proliferative defect in response to LPS, a moderate defect in response to CD40 ligand (CD40L), and normal proliferation to Ag receptor cross-linking using dextran-conjugated anti-IgD Abs (alpha delta-dex), B cells lacking both p50 and p65 exhibited severely impaired proliferation in response to LPS, alpha delta-dex, and CD40L. This defect could be overcome by simultaneous administration of alpha delta-dex and CD40L. In response to this latter combination of stimuli, B cells lacking both p50 and p65 secreted Ig and underwent isotype switching to IgG1 as efficiently as B cells lacking p50 alone. These data demonstrate a role for the p65 subunit of NF-kappa B in germline CH gene expression as well as functional redundancy between p50 and p65 during proliferative responses.


Assuntos
Linfócitos B/metabolismo , Switching de Imunoglobulina , Regiões Constantes de Imunoglobulina/genética , Imunoglobulina G/biossíntese , Ativação Linfocitária , NF-kappa B/fisiologia , Transcrição Gênica/imunologia , Animais , Linfócitos B/imunologia , Divisão Celular/genética , Divisão Celular/imunologia , Células Cultivadas , Feminino , Switching de Imunoglobulina/genética , Cadeias Pesadas de Imunoglobulinas/genética , Ativação Linfocitária/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos , Camundongos Knockout , NF-kappa B/deficiência , NF-kappa B/genética , Subunidade p50 de NF-kappa B , Fator de Transcrição RelA
4.
J Immunol ; 159(7): 3133-9, 1997 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-9317110

RESUMO

The Ig heavy chain locus contains a number of binding sites for the transcriptional activator, c-Rel. In this study, we evaluated the capacity of B cells from mice made genetically deficient in the C-terminal, transactivation domain of the c-Rel protein (delta c-Rel) to undergo Ig class switching. Flow-cytometric and digestion circularization PCR analyses revealed that delta c-Rel B cells failed to switch to IgG3 in response to LPS alone, or to IgG1 or IgE in response to LPS + IL-4. This failure to switch to IgG3 or IgG1 was associated with a corresponding loss of germline CH gamma 3 or CH gamma 1 RNA. However, the defective switching to IgE in delta c-Rel B cells was associated with normal levels of germline CH epsilon RNA relative to control B cells. The ability of delta c-Rel B cells to switch to IgG1, in response to LPS + IL-4, could be restored through the action(s) of additional stimuli, and this was associated with induction of normal levels of germline CH gamma 1 RNA relative to controls. In contrast, LPS-activated B cells from delta c-Rel mice underwent normal switching to IgA in the presence of TGF-beta, relative to control B cells. This was associated with equivalent steady state levels of germline CH alpha RNA between the two B cell populations. These data are the first to demonstrate a key and selective role for c-Rel in the regulation of Ig class switching. Furthermore, distinct differences are revealed in the Ig isotype induction profiles of B cells lacking c-Rel activity vs those deficient in p50/nuclear factor-kappa B.


Assuntos
Linfócitos B/metabolismo , Switching de Imunoglobulina , Regiões Constantes de Imunoglobulina/genética , Cadeias Pesadas de Imunoglobulinas/genética , Proteínas Proto-Oncogênicas/deficiência , Proteínas Proto-Oncogênicas/genética , Transcrição Gênica/imunologia , Ativação Transcricional/imunologia , Animais , Linfócitos B/imunologia , Células Germinativas/imunologia , Imunoglobulina A/biossíntese , Imunoglobulina E/biossíntese , Imunoglobulina G/biossíntese , Cadeias alfa de Imunoglobulina/biossíntese , Cadeias épsilon de Imunoglobulina/biossíntese , Cadeias épsilon de Imunoglobulina/genética , Cadeias gama de Imunoglobulina/biossíntese , Cadeias gama de Imunoglobulina/genética , Lipopolissacarídeos/farmacologia , Ativação Linfocitária/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Estrutura Terciária de Proteína , Proteínas Proto-Oncogênicas/fisiologia , Proteínas Proto-Oncogênicas c-rel , RNA/biossíntese
5.
J Immunol ; 159(6): 2559-62, 1997 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-9300672

RESUMO

DNA-dependent protein kinase, the catalytic subunit associated with the Ku heterodimer (Ku70/Ku86), has been implicated in switch recombination. Therefore, we tested whether certain stimuli known to promote switch recombination may act in part by inducing Ku expression. We find that resting B cells contain relatively low levels of nuclear Ku, but that Ku expression can be up-regulated by culturing the cells with two switch stimuli. First, IL-4 and CD40 engagement in combination, but neither of these stimuli acting alone, strongly induce Ku expression; Ku levels rise within 24 h, about 2 days before switch recombination is detected. Second, dextran-conjugated anti-IgD Abs strongly induce Ku expression, which is variably enhanced by IL-5, but not by IL-4. Our data suggest that switch recombination may be regulated, at least in part, through changes in the nuclear expression of Ku.


Assuntos
Antígenos Nucleares , Linfócitos B/imunologia , DNA Helicases , Proteínas de Ligação a DNA/imunologia , Switching de Imunoglobulina , Proteínas Nucleares/imunologia , Transdução de Sinais/imunologia , Animais , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Interleucina-4/farmacologia , Interleucina-5/farmacologia , Autoantígeno Ku , Camundongos , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética
7.
J Exp Med ; 184(4): 1537-41, 1996 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-8879226

RESUMO

A number of distinct functional abnormalities have been observed in B cells derived from p50/ NF-kappa B or c-rel knockout mice. RelB, another member of the NF-kappa B/Rel family of transcription factors, is expressed during the latter stages of B cell maturation and can bind to regulatory sites within the Ig heavy chain locus. Therefore, we tested the ability of B cells from relB knockout mice (relB-/-) to proliferate, undergo maturation to IgM secretion, and switch to the expression of downstream Ig isotypes in response to distinct activators including LPS, anti-CD40 mAb or CD40 ligand, and/or dextran anti-IgD antibodies in combination with various cytokines, including IL-4, IL-5, IFN-gamma, and TGF-beta. B cells lacking RelB showed up to 4-fold reductions in DNA synthesis in response to LPS, CD40, and membrane Ig-dependent activation relative to controls. However, relB-/- B cells were comparable to control B cells in their ability to undergo maturation to IgM secretion and switch to the expression of IgG3, IgG1, IgG2b, IgG2a, IgE, and/or IgA under all activation conditions tested. Thus, RelB, like c-Rel and p50/NF-kappa B, plays a role in B cell proliferation. However, in contrast to c-Rel and p50/ NF-kappa B, it is not critically involved in maturation to Ig secretion or expression of Ig isotypes.


Assuntos
Linfócitos B/imunologia , Switching de Imunoglobulina , Isotipos de Imunoglobulinas/metabolismo , Ativação Linfocitária , Proteínas Proto-Oncogênicas/deficiência , Animais , Anticorpos/farmacologia , Linfócitos B/efeitos dos fármacos , Antígenos CD40/metabolismo , Diferenciação Celular , Citocinas/farmacologia , Imunoglobulina M/metabolismo , Lipopolissacarídeos/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas c-rel , Receptores de Antígenos de Linfócitos B/metabolismo , Fatores de Transcrição/deficiência
8.
Int Immunol ; 8(5): 781-90, 1996 May.
Artigo em Inglês | MEDLINE | ID: mdl-8671667

RESUMO

A role for IL-10 in regulating Ig isotype switching directly at the level of the murine B cell has not been previously reported. In this report we show that IL-10 selectively up-regulated IgM to IgG3 class switching in lipopolysaccharide (LPS)-activated cultures through a direct effect on membrane (m) IgM+IgG3(-)B cells in vitro. IL-10 stimulated a 3- to 4-fold enhancement (from 6-8 to 20-30%) in membrane mIgG3(+) cells and a significant increase in Smu-Sgamma3 DNA rearrangement events as measured by digestion-circularization PCR (DC-PCR) over that observed with LPS alone. IL-10 induction of switching to IgG3 was not accompanied by a corresponding increase in the steady-state levels of germline CHgamma3 RNA. By contrast, IL-10 strongly inhibited the transforming growth factor-beta-mediated generation of mIgA+ cells and Smu-Salpha DNA rearrangement events in LPS-, but not CD40 ligand (CD40L)-activated B cells. This effect was not accompanied by changes in the steady-state levels of germline CHalpha RNA. IL-10 had no effect on IL-4-mediated switching to either IgG1 or IgE in either LPS- or CD40L-activated B cells. Thus, IL-10 can either enhance or suppress switching to particular murine Ig isotypes but it differs from most other murine cytokines in that its effects on switching do not appear to be associated with changes in the corresponding steady-state levels of germline CH RNA.


Assuntos
Switching de Imunoglobulina/efeitos dos fármacos , Interleucina-10/farmacologia , Animais , Linfócitos B/efeitos dos fármacos , Antígenos CD40/farmacologia , Feminino , Imunoglobulina A/biossíntese , Imunoglobulina G/biossíntese , Imunoglobulina G/classificação , Imunoglobulina M/biossíntese , Interleucina-4/farmacologia , Lipopolissacarídeos/farmacologia , Camundongos , Camundongos Endogâmicos DBA , RNA Mensageiro/análise
9.
J Immunol ; 156(1): 183-91, 1996 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-8598461

RESUMO

To better understand the role of NF-kappaB in normal B cell physiology, we used a purified population of resting B cells from p50/NF-kappa B knockout (p50-/-) mice to determine their ability to proliferate, secrete Ig, express germ-line CHRNA, and undergo Ig isotype switching in vitro in response to a number of distinct stimuli. p50-/- B cells proliferated normally in response to dextran-anti-IgD Abs (alpha delta-dex) and membrane-bound, but not soluble, CD40 ligand (CD40), and they were virtually unresponsive to LPS when compared with control B cells. p50-/- B cells secreted markedly reduced Ig in response to alpha delta-dex or mCD40L in the presence of IL-4 + IL-5, despite their relatively normal proliferative rates, whereas normal Ig secretion was restored by the combination of alpha delta-dex and CD40L. p50-/- B cells expressed normal steady-state levels of germ-line CH gamma 1 and CH alpha RNA but markedly reduced germ-line CH gamma 3 and CH epsilon RNA upon appropriate stimulation. Although p50-/- B cells underwent substantial switching to IgG1, a marked reduction in the switch to IgG3 and IgE, as IgA, was observed. These data are the first to demonstrate key, independent roles for p50/NF-kappaB in normal B cell maturation to Ig secretion, germ-line CH gene activation, and Ig class switching, as well as mitogenesis, and provide a powerful and well-defined in vitro model system for studying the role of p50/NF-kappaB in a wide range of normal cellular functions.


Assuntos
Mutação em Linhagem Germinativa/imunologia , Switching de Imunoglobulina/genética , Regiões Constantes de Imunoglobulina/genética , Cadeias Pesadas de Imunoglobulinas/genética , Ativação Linfocitária/genética , NF-kappa B/genética , Transcrição Gênica/imunologia , Animais , Linfócitos B/efeitos dos fármacos , Linfócitos B/imunologia , Sequência de Bases , Antígenos CD40/imunologia , Antígenos CD40/farmacologia , Ligante de CD40 , Diferenciação Celular/genética , Diferenciação Celular/imunologia , Dextranos/farmacologia , Mutação em Linhagem Germinativa/efeitos dos fármacos , Imunoglobulina M/biossíntese , Imunoglobulina M/efeitos dos fármacos , Interleucina-4/farmacologia , Interleucina-5/farmacologia , Lipopolissacarídeos/farmacologia , Ativação Linfocitária/efeitos dos fármacos , Glicoproteínas de Membrana/farmacologia , Camundongos , Camundongos Knockout , Mitose/efeitos dos fármacos , Mitose/imunologia , Dados de Sequência Molecular , NF-kappa B/deficiência , Subunidade p50 de NF-kappa B , Transdução de Sinais/imunologia
10.
J Immunol ; 154(3): 1223-31, 1995 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-7529796

RESUMO

Cytokines are believed to regulate Ig class switching, in part, through selective modulation of germ-line constant heavy (CH) gene transcription. B cell activators such as LPS or activated T cell membranes also influence germ-line CH RNA expression in the absence of exogenous cytokines. In this report we determined whether multivalent Ag receptor cross-linking, utilizing dextran-conjugated anti-IgD Abs (alpha delta-dex), could also regulate germ-line CH RNA expression. We demonstrated that alpha delta-dex markedly inhibited germ-line epsilon RNA expression, but strongly augmented germ-line gamma 1 RNA, in LPS + IL-4-stimulated cultures. This was correlated with > 90% alpha delta-dex-mediated suppression in the secretion of IgE and generation of membrane (m)IgE+ cells, and a more modest 50% reduction in IgG1 synthesis and mIgG1+ cells. Furthermore, alpha delta-dex inhibited the LPS induction of both gamma 3 and gamma 2b germ-line RNA and the associated secretion of IgG3 and IgG2b. A similar alpha delta-dex-mediated suppression of germ-line gamma 2a RNA and IgG2a secretion in LPS + IFN-gamma-stimulated cultures was observed. By contrast, activation of resting B cells with alpha delta-dex alone led to induction of germ-line gamma 3, gamma 1, and gamma 2b RNA but did not stimulate detectable expression of RNA specific for gamma 2a or epsilon. These studies demonstrate that: 1) germ-line gamma 1 gene expression is regulated uniquely, 2) germ-line transcription and switch recombination can be dissociated, 3) the germ-line transcription of each IgG isotype has an independent pattern of regulation, and 4) cross-linking of the Ag receptor, by itself, can stimulate small amounts of germ-line CH RNA.


Assuntos
Regulação da Expressão Gênica/imunologia , Rearranjo Gênico do Linfócito B/imunologia , Switching de Imunoglobulina/imunologia , Animais , Linfócitos B/imunologia , Northern Blotting , Células Cultivadas , Dextranos/imunologia , Ensaio de Imunoadsorção Enzimática , Feminino , Regiões Constantes de Imunoglobulina/biossíntese , Imunoglobulina D/imunologia , Cadeias Pesadas de Imunoglobulinas/biossíntese , Interferon gama/fisiologia , Interleucina-4/fisiologia , Lipopolissacarídeos/farmacologia , Camundongos , Camundongos Endogâmicos DBA , RNA Mensageiro/biossíntese , Endonucleases Específicas para DNA e RNA de Cadeia Simples
11.
Neuroimmunomodulation ; 1(1): 59-65, 1994 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-8528886

RESUMO

The L-tryptophan eosinophilia myalgia syndrome (L-Trp-EMS), related to ingestion of impure L-Trp, occurred in epidemic proportions in the United States in 1989. Epidemiologic studies implicated 1,1'-ethylidenebis[L-tryptophan] (EBT) as the impurity most highly associated with development of human L-Trp-EMS. We have previously shown that Lewis (LEW/N) rats fed L-Trp implicated in the L-Trp-EMS epidemic (case-associated L-Trp) develop fasciitis and perimyositis which is associated with a reduction in corticotropin-releasing hormone (CRH) mRNA expression in the hypothalamic paraventricular nucleus (PVN). In this study, we report the effects of EBT- and case-associated L-Trp on CRH mRNA expression in the hypothalamic PVN and secretion of adrenocorticotropic hormone (ACTH) and corticosterone (CORT) into the plasma over a time course of 1-6 weeks in the same rats in which we have found fascial thickening and immune cell activation induced by these compounds. Both control L-Trp and EBT stimulated the secretion of ACTH and CORT at 1-2 weeks, whereas case-associated L-Trp did not. EBT and case-associated L-Trp decreased CRH mRNA expression in the PVN at 2-6 weeks, while control L-Trp had no effect. The striking contrast in the effects of case-associated L-Trp and EBT on the HPA axis suggests that the reduction in CRH mRNA levels in the PVN seen in each case may be related to different mechanisms. It is possible that EBT suppresses CRH mRNA expression directly, in the absence of inflammation, while case-associated L-Trp may act through multiple mechanisms, including that associated with inflammation.(ABSTRACT TRUNCATED AT 250 WORDS)


Assuntos
Encéfalo/metabolismo , Hormônio Liberador da Corticotropina/metabolismo , Síndrome de Eosinofilia-Mialgia/genética , Hipotálamo/metabolismo , RNA Mensageiro/biossíntese , Animais , Autorradiografia , Feminino , Expressão Gênica/genética , Ratos , Ratos Endogâmicos Lew , Fatores de Tempo
12.
Brain Res ; 631(1): 22-6, 1993 Dec 17.
Artigo em Inglês | MEDLINE | ID: mdl-8298992

RESUMO

The susceptibility of Lewis rats is related to blunted hypothalamic-pituitary-adrenal (HPA) axis responsiveness to a variety of inflammatory and neuroendocrine stimuli. In contrast resistance to inflammatory disease of histocompatible Fischer rats is associated with their intact HPA axis responses to the same stimuli. We have examined the contribution of IL-1 beta to in vitro corticotropin-releasing hormone (CRH) and arginine vasopressin (AVP) release from hypothalamic explants derived from LEW/N and F344/N rats. The same animal model has been used to investigate the regulatory effect of alpha MSH, an immunosuppressive neurohormone, on IL-1 beta stimulated CRH and AVP secretion. CRH basal release in both strains was similar. However, LEW/N hypothalamic AVP basal secretion was significantly elevated. CRH relative response of LEW/N hypothalamic explants to IL-1 beta stimulation was lower compared to Fischer, which is consistent with their hyporesponsiveness to inflammatory mediators. AVP secretion however, was significantly decreased in hypothalamic explants from both strains after 40 min exposure to IL-1 beta. alpha MSH suppressed basal CRH and AVP release in both LEW/N and F344/N rats and prevented IL-1 beta stimulated CRH secretion in these strains. AVP was further diminished in F344/N explants following incubation with alpha MSH + IL-1 beta, while LEW/N level was significantly elevated. However, AVP levels remained significantly below baseline in explants from both strains after final incubation with IL-1 beta. Although our findings indicate a modulatory action of alpha MSH in HPA axis regulation in vitro, the physiological importance of this phenomenon in Lewis and Fischer rats requires further investigation.


Assuntos
Arginina Vasopressina/metabolismo , Hormônio Liberador da Corticotropina/metabolismo , Hipotálamo/metabolismo , Interleucina-1/farmacologia , alfa-MSH/farmacologia , Animais , Suscetibilidade a Doenças , Feminino , Técnicas In Vitro , Inflamação , Ratos , Ratos Endogâmicos F344 , Ratos Endogâmicos Lew
13.
J Pharmacol Exp Ther ; 266(2): 1029-35, 1993 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-8355179

RESUMO

The L-tryptophan eosinophilia myalgia syndrome (L-TRP-EMS), an inflammatory syndrome characterized by eosinophilia, myalgias, perimyositis, fasciitis and neuropathies, occurred in epidemic proportions in the United States in the summer and fall of 1989. The neuropathic clinical features in L-TRP EMS are complex and mixed. In the present study, one of the impurities most highly associated with development of L-TRP EMS, 1,1'-ethylidenebis[L-tryptophan] (EBT), and two of its diastereoisomeric breakdown products, were compared for evidence of neurotoxicity in vitro. In 1-month-old spinal cord cultures derived from fetal mice, synthetic (-)-(1S,3S)-1-methyl-1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acid (1S-beta-C) produced a 30 to 35% loss in numbers of neurons. Toxicity was not apparent after treatment with the R-isomer of the same compound or with the parent compound, EBT. Cotreatment of cultures with 1S-beta-C and neutralizing antiserum to interleukin-1 alpha (IL-1 alpha), or with 1S-beta-C and neutralizing antiserum against the murine IL-1 receptor, prevented neuronal cell death associated with 1S-beta-C. Recombinant IL-1 alpha also produced neuronal killing that was not additive to that observed with the 1S-beta-C treatment. In contrast, in immature spinal cord neuronal cultures, the 1S-beta-C, but not the 1R-beta-C or EBT, prevented the 30% cell death which normally occurs in these cultures. Neither neutralizing anti-IL-1 antibody, nor anti-IL-1 receptor antibody blocked the neuronal survival effect, suggesting that 1S-beta-C induces neuronal survival through a receptor-mediated mechanism independent of IL-1.(ABSTRACT TRUNCATED AT 250 WORDS)


Assuntos
Carbolinas/toxicidade , Contaminação de Medicamentos , Síndrome de Eosinofilia-Mialgia/etiologia , Interleucina-1/fisiologia , Medula Espinal/efeitos dos fármacos , Triptofano/análogos & derivados , Animais , Morte Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Feminino , Camundongos , Gravidez , Receptores de Interleucina-1/fisiologia , Proteínas Recombinantes/farmacologia , Estereoisomerismo , Triptofano/toxicidade
14.
Neuroendocrinology ; 56(4): 474-82, 1992 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-1335552

RESUMO

We have previously shown that susceptibility to inflammatory disease in Lewis (LEW/N) rats is related to their limited hypothalamic-pituitary-adrenal (HPA) axis responses to a variety of inflammatory stimuli, while the relative resistance to inflammatory disease in Fischer (F344/N) rats is related to their potent HPA axis responses to these same stimuli. In vivo studies also showed that LEW/N pituitary ACTH responses to exogenous corticotropin-releasing hormone (CRH) were blunted compared to F344/N. To determine if there is a fundamental difference in pituitary corticotroph function between the two strains, independent of other factors influencing the HPA axis, we compared ACTH responses to a variety of stimuli in LEW/N and F344/N primary pituitary cell cultures. Here we show that in vitro basal ACTH secretion and peak ACTH response to CRH, forskolin and 8-bromo-cAMP are 50% lower in LEW/N than F344/N rats. However, these findings can be explained by other observations: diminished basal ACTH content, POMC mRNA, and a decreased number of corticotrophs, in pituitary cell cultures from LEW/N compared to F344/N rats. In addition, LEW/N corticotrophs were more sensitive to dexamethasone and to corticosterone suppression of CRH-stimulated ACTH secretion compared to F344/N. The data support the possibility of an HPA axis defect in LEW/N rats at the pituitary level which could be secondary to prolonged understimulation by hypothalamic CRH, or could also be partially related to enhanced glucocorticoid feedback inhibition.


Assuntos
8-Bromo Monofosfato de Adenosina Cíclica/farmacologia , Hormônio Adrenocorticotrópico/metabolismo , Hormônio Liberador da Corticotropina/farmacologia , Glucocorticoides/farmacologia , Inflamação/fisiopatologia , Hipófise/metabolismo , Animais , Células Cultivadas , Colforsina/farmacologia , Suscetibilidade a Doenças , Retroalimentação , Feminino , Hipófise/citologia , Hipófise/efeitos dos fármacos , Pró-Opiomelanocortina/genética , RNA Mensageiro/biossíntese , Ratos , Ratos Endogâmicos F344 , Ratos Endogâmicos Lew
15.
Endocrinology ; 131(3): 1453-7, 1992 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-1505475

RESUMO

The susceptibility of Lewis (LEW/N) rats to severe inflammatory disease has been causally associated with subnormal responsiveness of their hypothalamic CRH-secreting neurons and, consequently, their hypothalamic-pituitary-adrenal axis to several stimulatory neurotransmitters and inflammatory cytokines. In the present study we investigated in this strain the secretory dynamics of another major activator of pituitary ACTH secretion, arginine vasopressin (AVP). To accomplish this, we evaluated the circadian plasma concentrations and circadian and glucocorticoid-induced changes in hypothalamic content and in vitro release of AVP in 8- to 10-week-old female LEW/N rats and compared these measurements to those obtained in parallel from age- and sex-matched histocompatible, inflammatory disease-resistant Fischer (F344/N) rats. Plasma concentrations and hypothalamic content and in vitro release of AVP were significantly elevated in LEW/N compared to F344/N rats in both the morning and evening. These indices of higher AVP secretion in LEW/N than in F344/N rats were also present after chronic dexamethasone treatment. These findings suggest increased AVP production and release in LEW/N rats, perhaps representing an adaptive compensation for insufficient CRH and glucocorticoid secretion. The high levels of circulating AVP might contribute to the excessive inflammatory responses of these animals.


Assuntos
Arginina Vasopressina/metabolismo , Hormônio Liberador da Corticotropina/deficiência , Hormônio Liberador da Corticotropina/metabolismo , Hipotálamo/metabolismo , Inflamação/fisiopatologia , Análise de Variância , Animais , Arginina Vasopressina/sangue , Ritmo Circadiano , Dexametasona/farmacologia , Feminino , Hipotálamo/efeitos dos fármacos , Inflamação/genética , Técnicas de Cultura de Órgãos , Radioimunoensaio , Ratos , Ratos Endogâmicos F344 , Ratos Endogâmicos Lew , Especificidade da Espécie
16.
Neuroendocrinology ; 50(2): 236-9, 1989 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-2506485

RESUMO

The effect of synthetic human growth hormone-releasing hormone (GHRH) on chemotactic response and migration inhibition of human peripheral blood leukocytes has been studied. In the assay performed by using modified Nelson methods, significant inhibition of chemotactic response was observed at 10(-6)M-10(-8) M concentrations of GHRH. There is a strong negative correlation (r = -0.519; p less than 0.001) between the chemotactic response of peripheral blood leukocytes and the concentration of GHRH. In contrast, GHRH tested at the same concentration range was not active in the migration inhibition assay. This finding provides additional evidence for the neuroimmunomodulatory action of GHRH.


Assuntos
Inibição de Migração Celular , Quimiotaxia de Leucócito/efeitos dos fármacos , Hormônio Liberador de Hormônio do Crescimento/farmacologia , Neuroimunomodulação , Relação Dose-Resposta a Droga , Humanos , Fragmentos de Peptídeos/farmacologia , Fator de Necrose Tumoral alfa/farmacologia
17.
Neuropeptides ; 13(2): 75-7, 1989.
Artigo em Inglês | MEDLINE | ID: mdl-2567973

RESUMO

The effect of somatostatin 1-14 (SS) on the natural killer (NK) activity of human peripheral blood lymphocytes was investigated. The NK activity was estimated by means of radioactive chromium (51Cr) assay with the use of human leukemia cells K 562 as targets. The previous exposure of lymphocytes obtained from healthy donors to somatostatin in the concentration of 10(-8) and 10(-6) M resulted in the enhancement of NK activity. The finding provides a further evidence of the immunomodulating somatostatin action.


Assuntos
Células Matadoras Naturais/efeitos dos fármacos , Somatostatina/farmacologia , Adulto , Radioisótopos de Cromo/análise , Relação Dose-Resposta a Droga , Feminino , Humanos , Células Matadoras Naturais/imunologia , Leucemia/imunologia , Masculino , Células Tumorais Cultivadas
18.
J Pineal Res ; 7(2): 153-64, 1989.
Artigo em Inglês | MEDLINE | ID: mdl-2769568

RESUMO

One of the important immune functions influenced by neuroendocrine factors is natural killer (NK) activity, which is directed against neoplastic and virus-infected cells. The effects of melatonin (Mel) and N-acetylserotonin (NAc-5HT) on NK activity of human peripheral blood lymphocytes were investigated. Leukocytes of healthy human subjects were used in the experiment. NK activity was estimated by measurement of radioactive chromium (51Cr) release from human leukemia cells K 562 (target cells). The previous exposure of human lymphocytes (effector cells) to Mel in concentrations of 10(-6) M and 10(-10) M resulted in an inhibition of NK activity (P less than 0.01) for all the examined effector-target cell ratios (10:1; 20:1, 40:1). NK activity was also suppressed by Mel (10(-8) M), but only if effector-target ratio equal to 20:1 was used (P less than 0.02), and by Mel (10(-12) M) for effector-target ratio equal to 40:1 (P less than 0.05). In none of the examined concentrations did NAc-5HT inhibit NK activity of human lymphocytes. On the basis of the data reported above, a direct suppressive effect of Mel (but not of NAc-5HT) on NK activity of human peripheral blood lymphocytes can be assumed.


Assuntos
Células Matadoras Naturais/fisiologia , Melatonina/farmacologia , Células Cultivadas , Humanos , Células Matadoras Naturais/efeitos dos fármacos , Concentração Osmolar , Serotonina/análogos & derivados , Serotonina/farmacologia
19.
Brain Behav Immun ; 2(1): 50-6, 1988 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-3140923

RESUMO

The effect of corticoliberin (CRF) and somatoliberin (GRF) on the natural killer (NK) activity of human peripheral blood lymphocytes was investigated. NK activity was estimated by means of the radioactive chromium (51Cr) assay in which human leukemia K 562 cells serve as targets. Exposure of human lymphocytes (effector cells) to 10(-6) to 10(-10) M concentrations of CRF inhibited NK activity. NK activity was also suppressed by the same concentrations of GRF, but only when an effector:target cell ratio of 40:1 was used. In contrast, at effector:target ratios of 20:1 and 10:1, stimulatory effects of GRF were observed.


Assuntos
Hormônio Liberador da Corticotropina/farmacologia , Hormônio Liberador de Hormônio do Crescimento/farmacologia , Células Matadoras Naturais/efeitos dos fármacos , Testes Imunológicos de Citotoxicidade , Humanos
20.
Peptides ; 8(5): 951-2, 1987.
Artigo em Inglês | MEDLINE | ID: mdl-2893363

RESUMO

The effect of somatostatin-14 (SST) and somatostatin analog D-Phe-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH2 (RC-102) on migration inhibition of human leukocytes induced by cardiac antigen or phytohemagglutinin (PHA) was investigated. Both SST and RC-102 augmented the migration inhibition, thus indicating the enhanced formation or action of the leukocyte migration inhibiting factor (LMIF). This finding provides additional evidence for the immunomodulatory action of somatostatin.


Assuntos
Adjuvantes Imunológicos , Leucócitos/fisiologia , Somatostatina/análogos & derivados , Somatostatina/farmacologia , Movimento Celular/efeitos dos fármacos , Humanos , Técnicas In Vitro , Fatores Inibidores da Migração de Leucócitos/biossíntese , Leucócitos/efeitos dos fármacos , Somatostatina/imunologia
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