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PubMed1993

Modulation of murine cytokine responses to mycobacterial antigens by helminth-induced T helper 2 cell responses.

BALB/c mice inoculated with live Brugia malayi microfilariae (mf), or immunized with a soluble filarial extract (B. malayi Ag (BmA)), develop a pronounced Th2-like response over time. In contrast, single or repeated immunizations with a soluble Mycobacterium tuberculosis Ag preparation (purified protein derivative, PPD) stimulates a Th1, but not Th2 response (IFN-gamma >> IL-4, IL-5). To determine if the Th1 response to PPD can be modulated by the ongoing helminth-induced Th2 activity, mice were: 1) immunized simultaneously with BmA and PPD; 2) immunized first with BmA, then with PPD; or 3) inoculated with live mf and immunized with PPD at various times thereafter. Simultaneous immunization with both Ag had no effect on the Th response induced by PPD, i.e., it was strictly Th1. In contrast, establishment of a Th2 response by either inoculation of live mf or immunization with BmA before administration of PPD skewed the PPD-specific Th response such that IL-4 and IL-5 were produced in addition to IFN-gamma. IL-4 and IL-5 levels produced in response to PPD under these conditions were further elevated in vitro in the presence of neutralizing IFN-gamma. Finally, in vivo neutralization of IL-4 diminished induction of Th2 responses to PPD. These results demonstrate that ongoing Th2 responses to helminth Ag modulate the Th response to mycobacterial Ag by an IL-4 dependent mechanism.

Animals↗
PubMed1996

Detection of a kappa-casein-specific lymphocyte response in milk-responsive atopic dermatitis.

BACKGROUND: Bovine casein leads to an expansion of lymphocytes expressing the cutaneous lymphocyte antigen and to specific lymphocyte proliferation in a subgroup of patients with milk-responsive atopic dermatitis (AD). The casein fraction is composed of different proteins with defined and completely different sequences. OBJECTIVE: To define the stimulatory capacity of the major casein protein (alpha, beta and kappa) in lymphocyte proliferation assays with cells from milk-allergic and non-allergic individuals. METHODS: Proliferative responses of peripheral blood mononuclear cells to lipopolysaccharide-depleted casein subfractions were measured by thymidine incorporation. Lymphocytes from milk-responsive patients with AD were compared with cells from non-responsive patients with AD and to non-atopic individuals. Atopic individuals with immediate symptoms following consumption of cow's milk were included as positive controls. Casein-specific T-cell clones (TCC) from four patients with milk-responsive AD were restimulated with unfractionated casein and kappa-casein. RESULTS: Higher proliferative responses to unfractionated casein and alpha-, beta- and kappa-casein were observed in milk-responsive patients compared with non-responders. Unfractionated casein and kappa-casein discriminated best between the milk-responsive patients with AD and non-responders. Twenty-five of 31 TCG from patients with milk-responsive AD reacted to the mixed casein preparation and kappa-casein. CONCLUSION: A pronounced kappa-casein-specific T-cell-mediated immune response is found in the blood of many patients with a history of milk-related exacerbation of AD.

Adolescent↗
PubMed1992

Effect of allergen inhalation on the maximal response plateau of the dose-response curve to methacholine.

Methacholine dose response curves (DRC) in asthmatic subjects are characterized by a leftward shift and increased maximal response. Allergen inhalation in atopic subjects shifts the DRC to the left, but the effect on the shape is unknown. This study was designed to investigate the effect of allergen inhalation on the maximal response plateau of the methacholine DRC in 16 atopic subjects; nine had mild asthma and seven had rhinitis. They were challenged with allergen and with control solutions in a single-blind design. Methacholine challenges (up to 199 mumol) were performed at baseline and 24 h after the control and allergen challenges. A plateau of the DRC was defined as a difference of less than 5% in FEV1 between the last two or more doses. The maximal response was obtained by averaging the values on the plateau and was reached by all except one subject. Allergen inhalation induced an early asthmatic response (EAR) in all subjects and an additional late asthmatic response (LAR) in 6 subjects. In subjects with an EAR alone the maximal response to methacholine 24 h after allergen challenge was not different from control (mean difference, 2.9% fall in FEV1; p greater than 0.05). In subjects with LAR, the mean value for the maximal response increased from 28.5% after control to 36.5% after allergen (mean difference, 8.0%; p less than 0.05). Of six subjects who developed LAR two lost the plateau on the DRC after allergen challenge. We conclude that allergen inhalation increases the maximal response to methacholine in those subjects who have a LAR.

Administration, Inhalation↗
PubMed1991

v-Src activates mitogen-responsive transcription factor Egr-1 via serum response elements.

Activating the protein-tyrosine kinase activity of v-Src in murine fibroblasts leads to increased expression of Egr-1, a mitogen-responsive transcription factor. v-Src-induced expression of Egr-1 is independent of protein synthesis and is controlled at the level of transcription. Target sequences responsive to v-Src-induced signals were investigated using deletion mutant and analysis of the Egr-1 promoter. Upstream Egr-1 promoter sequences linked to a reporter gene were cotransfected with a v-Src expression vector into NIH 3T3 cells. v-Src-enhanced gene expression from the Egr-1 promoter was dependent upon the presence of CC(A/T)6GG elements. The CC(A/T)6GG motif forms the core element of serum response elements (SREs) and is the binding site for serum response factor. The Egr-1 promoter sequences responsive to v-Src contained four SREs. Sequential deletion of these SREs reduced v-Src responsiveness to basal transcription levels. A single SRE from this region was able to confer v-Src responsiveness to a heterologous promoter, and a mutation to the CC(A/T)6GG box of this SRE abolished v-Src-enhanced gene expression. Thus, an early response of v-Src-induced intracellular signaling is the transcriptional activation of a growth factor-responsive transcription factor via an SRE.

Animals↗
PubMed2006

Proteasome inhibition induces differential heat shock protein response but not unfolded protein response in HepG2 cells.

Liver, a central organ responsible for the metabolism of carbohydrates, proteins, and lipoproteins, is exposed to various kinds of physiological, pathological, and environmental stresses. We hypothesized that blockage of proteasome degradation pathway induces heat shock protein (HSP) response and unfolded protein response in the liver cells. In this study, we have characterized cellular responses to proteasome inhibition in HepG2 cells, a well-differentiated human hepatoma cells. We found that proteasome inhibition induced differential response among cytosolic HSPs, that is, increased expression of HSP70, but no change in HSP40, HSC70, and HSP90. However, proteasome inhibition did not induce typical unfolded protein response as indicated by absence of stimulation of GRP78 and GRP94 proteins. Upon proteasome inhibition, inclusion bodies were accumulated, and ubiquitin-conjugated proteins appeared in insoluble fraction, together with HSP40, HSP70, HSC70, and HSP90. After proteasome inhibition, misfolded proteins were increased in the cytosol and in the ER compartment as evaluated by examining ubiquitin-conjugated proteins. However, essentially all ER-associated ubiquitin-conjugated proteins were located on the surface of the ER, which explains why proteasome inhibition does not induce unfolded protein response. In conclusion, proteasome inhibition induces differential HSP response, but not unfolded protein response in HepG2 cells. Our study also suggests that HSPs play important roles in directing proteasomal degradation and protein aggregate formation.

3T3-L1 Cells↗
PubMed2005

Response execution, selection, or activation: what is sufficient for response-related repetition effects under task shifting?

Repetition effects are often helpful in revealing information about mental structures and processes. Usually, positive effects have been observed when the stimuli or responses are repeated. However, in task shift studies it has also been found that response repetitions can produce negative effects if the task shifts. Although several mechanisms have been proposed to account for this interaction between task shifting and response repetition, many details remain open. Therefore, a series of four experiments was conducted to answer two questions. First, are motor responses necessary to produce response-related repetition effects, or is response activation sufficient? Second, does the risk of an accidental re-execution of the last response affect the repetition costs? The results show that response activation alone can produce repetition effects. Furthermore, the risk of accidental response re-execution largely modulates these effects.

Adult↗
PubMed1982

Methacholine-induced cutaneous flare response: bivariate analysis of responsiveness and sensitivity.

Cutaneous reactions to allergens exhibit a sigmoid dose-response relationship. Available methods for evaluating the allergen skin-test response do not adequately account for the sigmoid curve. Methodologic factors handicap quantitative studies of allergens based on skin-test reactivity. This problem was evaluated with a pharmacologic agonist that mimics cutaneous reactivity. Epicutaneous tests with appropriate concentrations of methacholine were used to provoke flare responses in 84 healthy subjects. A novel hyperbolic tangent model of the sigmoid dose-response curve was used to estimate responsiveness (R) as the midpoint of the sigmoid curve. Sensitivity (C) was estimated as the agonist concentration yielding a flare response equivalent to R. Estimates of sensitivity were independent of estimates of responsiveness (r=-0.0565, p=0.6642). The geometric mean methacholine sensitivity among health subjects was 287 mM/L, and average methacholine responsiveness was 4.9 mm. The mathematic model used in these studies fitted observations surprisingly well (X2(84)=37.044, p greater than 0.95). Differences in methacholine sensitivity and responsiveness related to race, sex, and allergic and/or vasomotor tendencies were detected but were subtle and did not account for a significant portion of the variation among healthy subjects. This model may provide a useful method for quantifying cutaneous immediate hypersensitivity reactions in patients.

Adolescent↗
PubMed2006

Assessment of the ovine acute phase response and hepatic gene expression in response to Escherichia coli endotoxin.

Lipopolysaccharide (LPS), a bacterial membrane endotoxin, induces a systemic inflammatory response (IFR) through the activation of blood monocytes and hepatic kupffer cells. These cells secrete pro-inflammatory cytokines, which subsequently activate the hypothalamic-pituitary-adrenal axis (HPAA) to release cortisol, an anti-inflammatory hormone that regulates the IFR and subsequent immune response (IR). The intent of this study was to characterize the acute phase response in female sheep challenged systemically with a range of doses of Escherichia coli endotoxin. Yearling ewes were challenged with an i.v. bolus dose of LPS (0, 200, 400, 600 ng/kg BW) and the acute phase response assessed by measuring serum interleukin (IL)-6 and cortisol concentrations, and the febrile response over time. A follow-up liver biopsy study was performed to determine kinetic differences in the expression of eight candidate hepatic genes between LPS dose groups using real-time RT-PCR. The initial time trail did not follow a linear dose response relationship with respect to the febrile and HPAA response to LPS challenge. Serum IL-6 concentrations increased in the two highest treatment groups but did not correlate with the observed febrile and HPAA response. The expression of Toll-like receptor 4, CD14, IL-6, tumor necrosis factor-alpha, IL-1beta, macrophage migration inhibitory factor, 11-beta-hydroxysteroid dehydrogenase (HSD), and tachykinin precursor 1 hepatic genes was dependent on both the dose and the kinetics of the response to LPS.

Acute-Phase Reaction↗
PubMed1999

CCAAT/enhancer-binding protein beta is an accessory factor for the glucocorticoid response from the cAMP response element in the rat phosphoenolpyruvate carboxykinase gene promoter.

The cyclic AMP response element (CRE) of the rat phosphoenolpyruvate carboxykinase (PEPCK) gene promoter is required for a complete glucocorticoid response. Proteins known to bind the PEPCK CRE include the CRE-binding protein (CREB) and members of the CCAAT/enhancer-binding protein (C/EBP) family. We took two different approaches to determine which of these proteins provides the accessory factor activity for the glucocorticoid response from the PEPCK CRE. The first strategy involved replacing the CRE of the PEPCK promoter/chloramphenicol acetyltransferase reporter plasmid (pPL32) with a consensus C/EBP-binding sequence. This construct, termed pDeltaCREC/EBP, binds C/EBPalpha and beta but not CREB, yet it confers a nearly complete glucocorticoid response when transiently transfected into H4IIE rat hepatoma cells. These results suggest that one of the C/EBP family members may be the accessory factor. The second strategy involved co-transfecting H4IIE cells with a pPL32 mutant, in which the CRE was replaced with a GAL4-binding sequence (pDeltaCREGAL4), and various GAL4 DNA-binding domain (DBD) fusion protein expression vectors. Although chimeric proteins consisting of the GAL4 DBD fused to either CREB or C/EBPalpha are able to confer an increase in basal transcription, they do not facilitate the glucocorticoid response. In contrast, a fusion protein consisting of the GAL4 DBD and amino acids 1-118 of C/EBPbeta provides a significant glucocorticoid response. Additional GAL4 fusion studies were done to map the minimal domain of C/EBPbeta needed for accessory factor activity to the glucocorticoid response. Chimeric proteins containing amino acid regions 1-84, 52-118, or 85-118 of C/EBPbeta fused to the GAL4 DBD do not mediate a glucocorticoid response. We conclude that the amino terminus of C/EBPbeta contains a multicomponent domain necessary to confer accessory factor activity to the glucocorticoid response from the CRE of the PEPCK gene promoter.

Animals↗
PubMed2005

AUXIN RESPONSE FACTOR7 restores the expression of auxin-responsive genes in mutant Arabidopsis leaf mesophyll protoplasts.

AUXIN RESPONSE FACTOR7 (ARF7) is one of five ARF transcriptional activators in Arabidopsis thaliana that is proposed to regulate auxin-responsive expression of genes containing TGTCTC auxin response elements in their promoters. An Arabidopsis mutant (nonphototropic hypocotyl4-1 [nph4-1]) that is a null for ARF7 showed strongly reduced expression of integrated auxin-responsive reporter genes and natural genes that were monitored in Arabidopsis leaf mesophyll protoplasts. Expression of the reporter and natural genes was restored in an auxin-dependent manner when protoplasts were transfected with a 35S:ARF7 effector gene, encoding a full-length ARF7 protein. Transfection of effector genes encoding other ARF activators restored auxin-responsive gene expression to varying degrees, but less than that observed with the ARF7 effector gene. Arabidopsis lines that were null for ARF6, ARF8, or ARF19 were not defective in expression of the reporter and natural auxin response genes assayed in mesophyll protoplasts, suggesting that ARF7 plays a major role in regulating expression of a subset of auxin response genes in leaf mesophyll cells. Auxin-responsive gene expression was induced in wild-type protoplasts and restored in nph4-1 protoplasts only with auxin and not with other hormones, including brassinolide. In the presence of auxin, however, brassinolide modestly enhanced auxin-responsive gene expression.

Arabidopsis↗
PubMed1985

Female popliteal lymph node responses to H-Y antigen on male thymocytes in mice. I. Regulation of primary and secondary responses by H-2-associated Ir genes.

H-2-linked genes which control popliteal lymph node (PLN) immune responses to the H-Y antigen were analysed. It was found that at least two genes or two groups of genes are involved in the genetic control and are responsible for the four variants of relations observed between the primary and the secondary response: +/-, +/+, -/+ and -/- ('+' and '-' stand for a high and a low response, respectively). The results obtained with H-2 recombinant haplotypes indicated that the genes controlling the primary and secondary responses map to the left and to the right of the E alpha locus, respectively. A high primary response was observed in the presence of b alleles at K, A beta, A alpha, and E beta loci, whereas a high secondary response occurred only in the presence of d alleles in the chromosomal segment between E alpha and D loci. From the experiments with F1 hybrids it is clear that low secondary responses are, for the most part, dominant and that the two seemingly separate control mechanisms for the primary and secondary responses may interact.

Animals↗
PubMed1993

[Auditory steady-state response to sinusoidally amplitude-modulated tones. First report: investigation of response in the awake state].

Basic characteristics of the steady state response (SSR) evoked by sinusoidally amplitude-modulated tone (SAM tone) were studied in 26 awake adults with normal hearing. This study was designed to determine how this response to SAM tone effects the objective hearing test. The responses to 2048 stimuli were averaged with an analysis time set at 102.4 ms and were digitally filtered with a pass band of 30-100 Hz. The results obtained are as follows. With a carrier frequency of 500 Hz, the response amplitude was maximal at a modulation frequency of 30 or 40 Hz and decreased rapidly at 50 Hz. The response amplitude increased linearly with an increase in the modulation depth shown on a logarithmic scale. The mean latency of this response, as determined by the Diamond method, was 37.5 ms. The response amplitude increased with an increase in the stimulus intensity, but the rate of increase was highest at a carrier frequency of 500 Hz and tended to become smaller with increasing carrier frequency. At carrier frequencies of 500 and 1000 Hz, response detectability reached 100% with a stimulus intensity of 30 dBnHL, while at the higher frequencies, 100% detectability was attained at 40-50 dBnHL. The mean response thresholds were 15.0 dBnHL, 13.1 dBnHL, 25.3 dBnHL and 30.0 dBnHL at 500, 1000, 2000 and 4000 Hz, respectively.

Acoustic Stimulation↗
PubMed1992

The hamster immune response to tick-transmitted Borrelia burgdorferi differs from the response to needle-inoculated, cultured organisms.

The human immune response to natural infection with Borrelia burgdorferi appears to differ from that seen in small mammals infected by needle inoculation. In humans, antibody to outer surface proteins A and B (OspA and OspB) is not detectable until late in infection, but small mammals inoculated with B. burgdorferi produce early antibody to OspA and OspB. To investigate this disparity we compared the immune response in hamsters to B. burgdorferi after needle inoculation with cultured organisms or infected tick homogenates with the immune response after tick transmitted (natural) infection. We determined that the antibody response to OspA and OspB after natural infection of hamsters is similar to that seen in humans, and differs from the antibody response after hamster infection by needle inoculation. High titers of antibody to OspA and OspB were undetectable even 42 wk after bite by B. burgdorferi-infected ticks. The failure to produce antibody to OspA and OspB was not dependent on challenge dose, because animals inoculated by needle with low doses (1 x 10(5) to 1 x 10(6) cells) of B. burgdorferi produced antibody to OspA and OspB. A rapid but limited anti-41-kDa response was observed. One possible new Ag, 43 kDa (p43), was identified. The antibody response to p43 was independent of the route of inoculation. Our results suggest that the hamster immune response to tick-transmitted Borrelia burgdorferi differs from the response to needle inoculated, cultured organisms.

Animals↗
PubMed1982

Genetic regulation of the immune response to hepatitis B surface antigen (HBsAg). I. H-2 restriction of the murine humoral immune response to the a and d determinants of HBsAg.

In hepatitis B virus (HBV) infection correlation of disease activity with major histocompatibility complex (MHC) antigens has been suggested. However, no data are available regarding the nature and regulation of the immune response to the surface viral protein (HBsAg). This consideration and the current emphasis on production of an HBV vaccine led us to investigate the humoral immune response to HBsAg in inbred strains of mice to assess genetic factors that may regulate the humoral anti-HBs response. Studies with H-2 congenic and noncongenic inbred strains revealed the T-dependent humoral immune responses to the group-specific a and subtype-specific d determinants of HBsAg are regulated by gene(s) mapping to the murine MHC. The H-2q haplotype conferred high responsiveness, the H-2s,f haplotypes conferred low to nonresponsiveness, and the H-2a,b,d,k haplotypes were intermediate. Studies of H-2 recombinant strains allowed tentative mapping of regulation of the anti-a response and possibly the anti-d response to the K/I-A, I-B region of the MHC. The H-2-restricted regulation of the humoral immune response to HBsAg was circumvented by immunization with 10-fold higher HBsAg doses. These findings demonstrate a clear linkage between the murine MHC and the regulation of the immune response to specific determinants on HBsAg.

Animals↗
PubMed1995

High dose interferon alpha-2b therapy for chronic hepatitis C: an open label study of the response and predictors of response.

OBJECTIVES: The current recommended dose of interferon (IFN) for chronic hepatitis C is 3 million units (m.u.) 3 times a wk for 6 months, although the optimal dose is uncertain. In an open label cohort format, we evaluated the response rate at 6 months, the relapse rate at 12 months, the predictors of response, and adverse effects in 34 patients (mean age 42.4 +/- 2.4 yr) with chronic hepatitis C who were treated with 5 m.u. IFN 3 times a wk for 6 months. RESULTS: Twenty-nine patients (85%) responded either totally (TR) or partially (PR), and five (15%) showed no response (NR). Of 18 TR, eight (45%) showed a sustained response (SR), and nine (50%) patients relapsed at 12 months of follow-up with an overall SR rate of 24%. Despite the high frequency of side effects (17-70%), all patients completed the treatment. Of interest, two of three PR treated for an additional 3-6 months with 7.5 m.u. of IFN became TR at 12 months. Univariate and multivariate analysis demonstrated that the known duration of hepatitis and/or abnormal ALT elevation was longer in responders (43.5 +/- 9.1 months) compared with NR (8.2 +/- 1.4 months) (p = 0.018). Age, alcohol abuse, mode of acquisition, transaminase levels, and liver histology did not differ significantly between responders and NR. HCV-RNA in serum by RT-PCR assay was performed in six TR and four PR pretreatment, immediately posttreatment, and 3-6 months later. Five TR showed disappearance of viral RNA posttreatment with reappearance at low concentrations in two patients who relapsed. In four PR, viral RNA was detectable at low concentrations posttreatment. CONCLUSIONS: 1) Higher dose IFN therapy yields higher response rates at 6 months than the dose currently recommended with acceptable toxicity, but does not improve the sustained response rate; 2) the only predictor of a favorable response in this study was a longer known duration of hepatitis/abnormal ALT elevations; 3) serum HCV-RNA levels often disappear with a total response and may be used to monitor the response to treatment and relapse.

Adult↗
PubMed2001

Response to levodopa treatment in dopa-responsive dystonia.

BACKGROUND: Dopa-responsive dystonia (DRD) is similar to Parkinson disease in that both disorders have impaired dopamine synthesis and respond to levodopa treatment. Dopa-responsive dystonia differs in that dopamine storage is intact in contrast to Parkinson disease in which it is markedly reduced. OBJECTIVE: To examine the short- and long-duration responses to levodopa dosing in subjects with DRD. METHODS: The response to brief infusions of levodopa was examined in 4 subjects with DRD and the effects of withdrawal of levodopa for 3 to 7 days studied in the 3 subjects receiving long-term levodopa therapy. Motor function was measured with tapping speed, Unified Parkinson's Disease Rating Scale motor score, and global dystonia score. RESULTS: The short-duration response to levodopa dosing seems to develop more slowly and persists longer in subjects with DRD than in subjects with Parkinson disease. Withdrawal of levodopa leads to a gradual decline in tapping speed and reemergence of dystonia over several days, similar to the rate of decay of motor function in Parkinson disease. The short- and long-duration responses were not clearly differentiated in DRD. CONCLUSIONS: This pilot study suggests that retained dopamine storage in DRD may prolong the short-duration response and blur the distinction of the short- and long-duration responses. The decline in motor function in DRD on withdrawal of long-term levodopa therapy resembles that in Parkinson disease, suggesting that a long-duration response, if it exists in DRD, is unrelated to dopamine storage.

Adult↗