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PubMed2005

Visceral and cutaneous sensory testing in patients with painful bladder syndrome.

AIMS: Our aims were to determine whether subjects with painful bladder syndrome (PBS) demonstrate characteristics of visceral pain syndromes: visceral hyperalgesia, expanded loci of referral of bladder sensation, increased bladder pain with repetitive filling, lower thresholds to cutaneous stimulation in relevant dermatomes, abnormal response to repetitive cutaneous stimulation in relevant dermatomes, and also to develop easily applied measures for PBS pain evaluation and management. METHODS: We recruited PBS subjects and control subjects with no bladder pain and with either stress urinary incontinence (SUI) or no incontinence. Subjects underwent three bladder fills up to maximum 300 ml and mapped bladder fullness/discomfort, rating any pain present. Cutaneous current perception thresholds (CPTs) were tested at 2000 Hz, 250 Hz, 5 Hz at C5, T6, T10, T12, S3 dermatomes. Repetitive supra-threshold stimulation in trains of 15 stimuli 2 sec apart were then administered to T12, S3 dermatomes. RESULTS: PBS subjects demonstrated hyperalgesia to bladder filling and tended to sense bladder discomfort at both suprapubic and vulvar/urethral sites. There was no difference in CPTs at any dermatome at any stimulating frequency. PBS and SI subjects tended not to habituate to repetitive stimuli, while asymptomatic controls tended to habituate to repetitive stimulation. CONCLUSIONS: PBS subjects demonstrate bladder hyperalgesia and may sense bladder discomfort at sites other than suprapubic. Rating of bladder discomfort and sensory mapping during cystometry usefully distinguishes between PBS subjects and controls.

Adult↗

PubMed1990

Taste as a highly discriminative system: a hamster intrapapillar single unit study with 18 compounds.

Seventy-nine single units were recorded with glass micropipettes applied onto taste pores of the anterior portion of the tongue in anesthetized hamsters. The receptive field of each recorded unit was located by iontophoretic stimulation applying either anodal or cathodal current (1-20 microA) to a non-stimulating solution of sodium cyclamate (5 mM). Different kinds of responses to iontophoretic stimulation were described. Eighteen chemical stimuli including sweet and bitter tastants for humans, and amino acids were locally applied to one papilla of the receptive field of 63 of these units. Stimulations were applied in a continuous flow (30 ml/min) in a small chamber. Response criterion was chosen as 2 S.D. above the mean activity recorded during the minute preceding the stimulus arrival. The low amplitude of single unit responses to chemicals is discussed by reference to the recording and stimulating techniques and compared to results of control experiments on whole nerve recordings and psychophysical experiments on human subjects. The importance of a high flow rate during continuous flow stimulation was demonstrated. The possible necessity of mechanical stimulation to facilitate taste responses was outlined. The sensitivity of units to stimuli applied either chemically or iontophoretically was not identical. Contrary to authors expectations, localized sensitivities for a few specific chemicals were disclosed. The response reproducibility to chemical stimulation was 84% (S.D. = 1.6%). chi 2 calculation, correspondence analysis and hierarchical clustering showed small distances between the two profiles representing the same stimulus or the two profiles representing the same unit, but great distances between profiles representing either different stimuli or different units. All stimuli are different from one another. Only 6 pairs of similar units were found among 63 units. Unit clusters could be found only if a few stimuli were considered but they vanished when all 18 stimuli were used in the calculation. The breadth of tuning of units ranged from 0.25 to 0.92 with a mean of 0.68. We show that the peripheral taste system is highly discriminative. Each stimulus evokes a distinct sensory image. At least 8 independent factors are needed to describe the peripheral taste space, setting a lower limit to the number of different peripheral information channels (putative acceptors) involved.

Action Potentials↗

PubMed1997

mGluR II agonist inhibition of LTP induction, and mGluR II antagonist inhibition of LTD induction, in the dentate gyrus in vitro.

The effects of the metabotropic glutamate receptor (mGluR) group II agonist (2S,1'R,2'R,3'R)-2-(2',3'-dicarboxycyclopropyl)glycine (DCG-IV) and the antagonist 2S,1S',2S'-2-methyl-2-(2'-carboxycyclopropyl)glycine (MCCG) on the induction of long-term potentiation (LTP) and long-term depression (LTD) of the field excitatory postsynaptic potential (epsp) in the dentate gyrus of the rat hippocampus were investigated in vitro. In control media, high frequency stimulation (HFS) consisting of a series of trains of stimuli at 200 Hz induced LTP, and low frequency stimulation (LFS) consisting of 900 stimuli at 1 Hz induced LTD. DCG-IV (50 nM) strongly inhibited the induction of LTP. The block of LTP induction was not caused by a frequency-dependent inhibition of the epsp during HFS, as the epsps evoked during HFS were not altered by DCG-IV. MCCG (500 microM) did not inhibit the induction of LTP, but did prevent the block of LTP by DCG-IV. MCCG (500 microM) strongly inhibited the induction of LTD. DCG-IV (50 nM) did not inhibit LTD induction.

Amino Acids, Dicarboxylic↗

PubMed1991

Effect of serotonin depletion by p-chlorophenylalanine upon discriminative behaviours.

1. Para-chlorophenylalanine (p-CPA), a competitive inhibitor of the serotonin (5-HT) synthesis enzyme tryptophan hydroxylase, was administered to rats at a dosage (100 mg/kg daily for 3 days) that depletes 5-HT. 2. Different groups of these rats were previously trained to discriminate the interoceptive stimuli produced by amphetamine, cathinone, 3,4-methylenedioxymethamphetamine (MDMA), N-ethyl-3,4-methylenedioxyamphetamine (MDE), fenfluramine or yohimbine, and the effect of p-CPA pretreatment upon their discriminative performance was compared with the effect of saline (control) pretreatment. 3. p-CPA was shown to have no effect upon the dopaminergically-mediated stimuli produced by the stimulants amphetamine and cathinone or upon yohimbine performance. 4. p-CPA significantly decreased discriminative performance with the serotonergic releasing drugs MDMA, MDE and fenfluramine. This decrease in discriminative performance returned to pre-p-CPA (criterion) levels at a time (9-12 days) when 5-HT has been reported to replete to normal brain concentrations. 5. It is concluded that p-CPA pretreatment lowers brain 5-HT and, in turn, significantly decreases the ability of rats to discriminate centrally active drugs whose interoceptive cueing stimuli are mediated by 5-HT neurons.

Animals↗

PubMed2001

Proinflammatory and regulatory cytokine production associated with innate and adaptive immune responses in children with autism spectrum disorders and developmental regression.

We determined innate and adaptive immune responses in children with developmental regression and autism spectrum disorders (ASD, N=71), developmentally normal siblings (N=23), and controls (N=17). With lipopolysaccharide (LPS), a stimulant for innate immunity, peripheral blood mononuclear cells (PBMCs) from 59/71 (83.1%) ASD patients produced >2 SD above the control mean (CM) values of TNF-alpha, IL-1beta, and/or IL-6 produced by control PBMCs. ASD PBMCs produced higher levels of proinflammatory/counter-regulatory cytokines without stimuli than controls. With stimulants of phytohemagglutinin (PHA), tetanus, IL-12p70, and IL-18, PBMCs from 47.9% to 60% of ASD patients produced >2 SD above the CM values of TNF-alpha depending on stimulants. Our results indicate excessive innate immune responses in a number of ASD children that may be most evident in TNF-alpha production.

Adaptation, Physiological↗

PubMed1986

Early olfactory learning induces an enhanced olfactory bulb response in young rats.

During postnatal days 1-18, pups were simultaneously exposed to an odor and reinforcing tactile stimulation similar to that normally received from the dam. Control pups received only the odor, only the stimulation, or neither of these stimuli. On postnatal day 19, pups that had previously received simultaneous odor and tactile stimulation displayed both a behavioral odor preference and an enhanced 2-deoxyglucose uptake in specific olfactory bulb glomeruli to subsequent presentation of that odor. These results suggest that early olfactory learning enhances the neural response to odors that have acquired attractive value.

Animals↗

PubMed1989

Effects of vagus nerve on heart rate and ventricular contractility in chicken.

We determined the effects of vagus nerve stimulation on cardiac cycle length and on ventricular contraction and relaxation in 18 chickens anesthetized with pentobarbital. Right vagus stimulation at a constant frequency of 35 Hz prolonged cycle length by 190%, whereas left vagus stimulation at the same frequency increased cycle length by 136%. When one burst of stimuli was delivered to the right vagus nerve each cardiac cycle, but the timing of the stimuli was changed within the cardiac cycle, the response of the avian pacemaker cells varied substantially with the timing of the stimuli. Right and left vagus stimulation at a constant frequency of 20 Hz depressed ventricular contraction by 62 +/- 6 and 52 +/- 6%, respectively, and depressed ventricular relaxation by 56 +/- 7 and 53 +/- 7%, respectively. These results indicate that in the chicken the chronotropic effects of right vagus stimulation are greater than those of left vagus stimulation, whereas right and left vagus stimulation are approximately equipotent on ventricular contraction and relaxation.

Animals↗

PubMed2005

Enhanced temporal summation of pressure pain in the trapezius muscle after delayed onset muscle soreness.

Temporal summation of muscle pain is an important factor in musculoskeletal pain as central integration of repetitive nociceptive input can be facilitated in musculoskeletal pain patients. The aim of this study is to evaluate changes in temporal summation of pressure pain after induction of delayed onset muscle soreness (DOMS) of the trapezius muscle. Sixteen healthy volunteers participated in the study. Temporal summation of pain was induced by sequential pressure stimulation by a computer-controlled algometer. Sequential stimulation consisting of ten stimuli (at pressure pain threshold intensity) was applied over the trapezius muscle. Stimulus duration was 1 s and inter-stimulus intervals (ISI) were 1, 5, 10, and 30 s, respectively. The pain was rated on a continuous visual analogue scale (VAS, 10 cm) after each stimulus and normalised to the VAS score from the first stimulus. DOMS was induced in the right trapezius muscle by eccentric shoulder exercises while the left trapezius muscle served as control. Temporal summation of pressure evoked pain was measured before and 24 h after the exercise. At 24 h after exercise, soreness intensity during shoulder elevation was 3.7+/-0.2 cm, while no soreness was observed on the control side. When sequential pressure stimulation was applied to the DOMS muscle, VAS scores for 1 s ISI progressively increased to a higher level than before exercise (VAS increase for the last stimulus: 0.8+/-0.2 cm vs. 0.6+/-0.1 cm, P<0.05), while VAS scores for ISI 5, 10, and 30 s were not increased. On the control side, significant increases in VAS scores was observed for all ISIs but not affected by contralateral DOMS. Facilitation of temporal summation for 1 s ISI indicated that DOMS may increase the central excitability besides involving peripheral sensitisation. During DOMS there was no potential for further nociceptor sensitisation by repeated noxious pressure stimuli, which may account for the diminishment of temporal summation evoked by pressure stimuli with ISI 5, 10, and 30 s. These data indicate that muscle soreness might facilitate the central components of temporal summation to mechanical stimulation.

Adult↗

PubMed1986

von Willebrand factor interaction with the glycoprotein IIb/IIa complex. Its role in platelet function as demonstrated in patients with congenital afibrinogenemia.

We have studied three afibrinogenemic patients, who had only trace amounts of plasma and platelet fibrinogen as measured by radioimmunoassay, and demonstrate here that the residual aggregation observed in their platelet-rich plasma is dependent upon von Willebrand factor (vWF) binding to the platelet membrane glycoprotein (GP)IIb/IIIa complex. The abnormality of aggregation was more pronounced when ADP, rather than thrombin, collagen, or the combination of ADP plus adrenaline was used to stimulate platelets. With all stimuli, nevertheless, the platelet response was completely inhibited by a monoclonal antibody (LJP5) that is known to block vWF, but not fibrinogen binding to GPIIb/IIIa. Addition of purified vWF to the afibrinogenemic plasma resulted in marked increase in the rate and extent of aggregation, particularly when platelets were stimulated with ADP. This response was also completely blocked by LJP5. Addition of fibrinogen, however, restored normal aggregation even in the presence of LJP5, a finding consistent with the knowledge that antibody LJP5 has no effect on platelet aggregation mediated by fibrinogen binding to GPIIb/IIIa. Two patients gave their informed consent to receiving infusion of 1-desamino-8-D-arginine vasopressin (DDAVP), a vasopressin analogue known to raise the vWF levels in plasma by two- to fourfold. The bleeding time, measured before and 45 min after infusion, shortened from greater than 24 min to 12 min and 50 s in one patient and from 16 min to 9 min and 30 s in the other. Concurrently, the rate and extent of ADP-induced platelet aggregation improved after DDAVP infusion. The pattern, however, reversed to baseline levels within 4 h. The concentration of plasma vWF increased after DDAVP infusion, but that of fibrinogen remained at trace levels. We conclude that vWF interaction with GPIIb/IIIa mediates platelet-platelet interaction and may play a role in primary hemostasis.

Adenosine Diphosphate↗

PubMed2003

Modulation of CD40L antigen expression in Jurkat cells: involvement of protein kinase C activity.

The CD40L expressed on activated CD4+ T cells delivers contact-dependent proliferative and anti-apoptotic signals to B lymphocytes. Little is known about molecular mechanisms of constitutive expression of CD40L on some non-Hodgkin's lymphomas, especially about involvement of two signal pathways regulating its expression in normal cells; one involving calcineurin, and the other protein kinase C. We analyzed by flow cytometry the effects of 6-hour stimulation of both pathways (stimuli: PMA and ionomycin) and their inhibitors: cyclosporin A and chelerythrine, on CD40L expression. Two Jurkat clones differing in CD40L surface expression: clone 217.6 (CD40L-) and 217.7 (CD40L+) were studied. Our experiments showed that high level of CD40L expression on the surface of 217.7 cells was reduced after stimulation with PMA. The same effect was observed for combination of PMA and chelerythrine or for PKC inhibitor alone. In 217.6 cells, only chelerythrine used alone induced low level of CD40L expression, while PMA and ionomycin were without effect. These results suggest that CD40L surface expression is mainly dependent on protein kinase C activity. By using PepTag Assay we have confirmed that in both Jurkat clones PKC activity is higher than in normal blood lymphocytes.

Alkaloids↗

PubMed1996

Prepulses inhibit startle-induced reductions of extracellular dopamine in the nucleus accumbens of rat.

In vivo brain microdialysis was used to monitor extracellular levels of dopamine (DA) in the nucleus accumbens (NAc) of rats during exposure to startling acoustic stimuli. Ten rats were prepared with guide cannulae into which dialysis probes were inserted 1 d before testing. Two to three hours after the start of perfusion, rats were placed into the startle chamber and exposed to a continuous 70 dB(A) background noise. Dialysis samples (2.0 microliter/min) were collected at 6 min intervals. Startle pulses (120 dB[A] noise) were presented in 20-trial blocks lasting 5 min. In some blocks, an 86 dB[A] prepulse preceded each of the 20 pulses by 100 msec, with the order of presentation of pulse-alone or prepulse + pulse blocks being counterbalanced between animals. Three to six sample periods intervened between stimulus-containing blocks. Monoamine and metabolite levels were measured using HPLC with electro-chemical detection. During the presentations of startling stimuli, DA levels in the NAc decreased relative to the immediately preceding 12 min baseline. This decrease in DA was maintained for only one additional sample period. By contrast, the presentation of prepulse + pulse trials failed to affect dialysate levels of NAc DA during or immediately after the stimulation. Thus, startling acoustic stimuli produce significant and transient decreases in dialysate levels of DA in the NAc. Furthermore, prepulse stimuli effectively inhibit these neurochemical effects of starting stimuli, in parallel with their establish ability to inhibit the amplitude the behavioral startle response.

3,4-Dihydroxyphenylacetic Acid↗

PubMed2003

Corollary discharge inhibition of ascending auditory neurons in the stridulating cricket.

Acoustically communicating animals are able to process external acoustic stimuli despite generating intense sounds during vocalization. We have examined how the crickets' ascending auditory pathway copes with self-generated, intense auditory signals (chirps) during singing (stridulation). We made intracellular recordings from two identified ascending auditory interneurons, ascending neuron 1 (AN1) and ascending neuron 2 (AN2), during pharmacologically elicited sonorous (two-winged), silent (one-winged), and fictive (isolated CNS) stridulation. During sonorous chirps, AN1 responded with bursts of spikes, whereas AN2 was inhibited and rarely spiked. Low-amplitude hyperpolarizing potentials were recorded in AN1 and AN2 during silent chirps. The potentials were also present during fictive chirps. Therefore, they were the result of a centrally generated corollary discharge from the stridulatory motor network. The spiking response of AN1 and AN2 to acoustic stimuli was inhibited during silent and fictive chirps. The maximum period of inhibition occurred in phase with the maximum spiking response to self-generated sound in a sonorously stridulating cricket. In some experiments (30%) depolarizing potentials were recorded during silent chirps. Reafferent feedback elicited by wing movement was probably responsible for the depolarizing potentials. In addition, two other sources of inhibition were present in AN1: (1) IPSPs were elicited by stimulation with 12.5 kHz stimuli and (2) a long-lasting hyperpolarization followed spiking responses to 4.5 kHz stimuli. The hyperpolarization desensitized the response of AN1 to subsequent quieter stimuli. Therefore, the corollary discharge will reduce desensitization by suppressing the response of AN1 to self-generated sounds.

Acoustic Stimulation↗

PubMed1973

Responses of respiratory neurons of the rabbit to some excitatory and inhibitory stimuli.

The effects of an afferent stimulation of the vagus nerve, hypercapnia and hyperventilation on the discharges of pontine, medullary and phrenic respiratory neurons were studied. The responses were investigated in spontaneously breathing, lightly anaesthetized rabbits with intact vagi, and subsequently during artificial ventilation, after vagotomy and under surgical anaesthesia. We found that the patterns of activity of respiratory neurons depend upon the integrity of vagal conduction, pattern of ventilation and depth of anaesthesia, and that vagotomy and deep anaesthesia markedly modify, and sometimes even reverse, the responses of these neurons to respiratory stimuli. The pre-vagotomy type of response can be restored by stimulating the central end of a cut vagus nerve with standard pulses triggered by action potentials recorded simultaneously from the animal respiratory unit. The significance of these findings is discussed.

Animals↗

PubMed1999

Cochlear and trigeminal systems contributing to the startle reflex in rats.

The startle reflex is evoked by strong acoustic or tactile stimuli, or by electrical stimulation of acoustic or tactile pathways. To dissociate the contributions of acoustic and tactile pathways, stimulating electrodes were placed in adjacent cochlear and trigeminal nuclei. The currents needed to evoke startle-like responses were an order of magnitude lower in ventral trigeminal sites (12-80 microA for a 0.1-ms pulse) than in cochlear nucleus sites (150-800 microA). At low threshold sites in both areas, brief acoustic stimuli were followed 0-4 ms later by a single electrical pulse and the current required to evoke startle was measured at several interstimulus intervals. Summation between the acoustic and electrical stimuli for startle was strong in both cochlear and trigeminal sites. Collision effects were found in the anteroventral cochlear nucleus when the electrical stimulus followed the ipsilateral acoustic stimulus by 2.0 ms, suggesting that acoustic startle is mediated by axons in the anteroventral cochlear nucleus. Collision effects were found at 4.0 ms if the electrical stimulus was presented in the contralateral pontine reticular formation, suggesting that acoustic signals mediating startle mainly cross to the pontine reticular formation. Collision effects were not found in medial or posterior sites in the cochlear nucleus, or trigeminal sites, suggesting that the neurons that mediate startle in these sites do not mediate acoustic startle. Therefore, acoustic startle is mediated through high threshold cochlear nucleus sites, while low threshold sites are non-acoustic, probably as a result of trigeminal or vestibular stimulation.

Acoustic Stimulation↗

PubMed1998

Gap detection as a measure of electrode interaction in cochlear implants.

Gap detection thresholds were measured as an indication of the amount of interaction between electrodes in a cochlear implant. The hypothesis in this study was as follows: when the two stimuli that bound the gap stimulate the same electrode, and thus the same neural population, the gap detection threshold will be short. As two stimuli are presented to two electrodes that are more widely separated, the amount of neural overlap of the two stimuli decreases, the stimuli sound more dissimilar, and the gap thresholds increase. Gap detection thresholds can thus be used to infer the amount of overlap in neural populations stimulated by two electrodes. Three users of the Nucleus cochlear implant participated in this study. Gap detection thresholds were measured as a function of the distance between the two electrode pairs and as a function of the spacing between the two electrodes of a bipolar pair (i.e., using different modes of stimulation). The results indicate that measuring gap detection thresholds may provide an estimate of the amount of electrode interaction. Gap detection thresholds were a function of the physical separation of the electrode pairs used for the two stimuli that bound the gap. Lower gap thresholds were observed when the two electrode pairs were closely spaced, and gap thresholds increased as the separation increased, resulting in a "psychophysical tuning curve" as a function of electrode separation. The sharpness of tuning varied across subjects, and for the three subjects in this study, the tuning was generally sharper for the subjects with better speech recognition. The data also indicate that increasing the separation between active and reference electrodes has limited effect on spatial selectivity (or tuning) as measured perceptually.

Acoustic Stimulation↗

PubMed1992

Simple reaction time to focal transcranial magnetic stimulation. Comparison with reaction time to acoustic, visual and somatosensory stimuli.

We studied the effect of different go-signals on the reaction time in nine normal human subjects trained to respond by rapidly flexing one arm. Reaction times to auditory stimuli were shorter than those to visual or somatosensory stimuli, and were inversely correlated with the stimulus intensity. The reaction time was longest to a transcranial (magnetic or electric) stimulus delivered over the contralateral motor cortex that was sufficiently strong to induce a motor evoked potential in the responding biceps. Conversely, reaction time was shortest to either subthreshold transcranial stimulation over the same scalp position or to transcranial stimulation over the ipsilateral motor cortex regardless of intensity. Suprathreshold transcranial stimulation to the motor cortex seems to transiently inhibit the neurons responsible for initiation of motor programs involving muscles in which motor evoked potentials have been induced, thereby prolonging the reaction time. On the other hand, a subthreshold stimulus either disinhibits or directly activates such neurons leading to a shorter reaction time. Transcallosal connections between the motor cortices may account for the short reaction time to ipsilateral transcranial stimulation.

Acoustic Stimulation↗

PubMed1989

Psychophysical observations on patients with neuropathic pain relieved by a sympathetic block.

Patients with sympathetically maintained pain (SMP) were tested with noxious heat pulses, innocuous mechanical stimuli, and transcutaneous electrical nerve stimulation before and during local anesthetic sympathetic blocks that relieved their pain. The perceived intensity of the pain evoked by these stimuli was measured by the patients' responses on a visual analog scale and compared to the responses obtained when the same stimuli were applied to contralateral normal skin. In 5 of 7 patients tested, graded noxious heat stimuli (43-51 degrees C) applied to painful skin resulted in heat-pain intensity ratings that were essentially identical to the responses obtained when the same stimuli were applied to the normal side. Of the remaining two patients, one was clearly hypoalgesic for heat-pain and the other was probably hyperalgesic. The normal and subnormal heat-evoked responses obtained from abnormal skin were unchanged during completely successful sympathetic blocks. Trains of noxious heat pulses (52 degrees C) evoked summation of the second pain sensation in each of the 4 patients tested. This summation effect was normal and unaffected by a sympathetic block. Four of the patients had allodynia evoked by mechanical stimulation. In each of the 3 allodynia cases tested, transcutaneous nerve stimulation at an intensity that was at threshold for detection evoked burning pain and a coexistent sensation of tingle, indicating that both sensations were due to the activation of A beta axons. Patients without touch-evoked pain reported that electrical stimuli at threshold for detection produced only the sensation of tingle. The pains evoked by touch and by threshold-strength nerve stimulation were eliminated during sympathetic block. In patients with allodynia, trains of gentle mechanical stimuli and trains of threshold-strength electrical nerve stimuli produced summation of the intensity of the burning pain sensation when the stimuli were presented at 0.3 Hz. These results add to a growing body of evidence indicating that the touch-evoked pain of some patients is due to abnormal central activity evoked by input from A beta low-threshold mechanoreceptors. The coexistence of A beta-evoked pain with normal heat-evoked pain and normal heat-pain summation suggests that the central abnormality cannot be a simple hypersensitivity of wide-dynamic-range neurons. The effect of sympathetic blockade on A beta-evoked pain and its summation suggests that the crucial sympathetic interaction may take place centrally. The results show that there is considerable heterogeneity of sensory abnormalities among patients with SMP.(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗

PubMed2004

Toll-like receptors differentially induce nucleosome remodelling at the IL-12p40 promoter.

Toll-like receptors (TLRs) mediate recognition of microbial components. Despite activation of a shared set of signal transduction molecules, the biological effects of certain TLR agonists differ considerably. In macrophages and dendritic cells, stimulation by the prototypical stimuli CpG-DNA (TLR9), lipopolysaccharide (LPS; TLR4) and lipoteichoic acid (LTA; TLR2) resulted in striking differences in expression of IL-12. However, these stimuli induced similar amounts of the common proinflammatory cytokine TNFalpha. Surprisingly, an IL-12p40 promoter reporter construct was activated equally by CpG-DNA, LPS and LTA. Examinations of the chromatin structure of the endogenous IL-12p40 promoter revealed that nucleosome remodelling contributed to differential IL-12 induction. Upon stimulation, nucleosome architecture was changed to provide increased access to the IL-12p40 promoter. In dendritic cells, a differential induction of nucleosome remodelling at the IL-12p40 promoter was observed upon triggering with different TLR agonists. These results identify nucleosome remodelling as an additional restriction point in differential TLR signalling.

Animals↗