Neuroendocrinology of acute immunity.

Bacterial endotoxins such as Escherichia coli lipopolysaccharide (LPS) bind to specific Toll-like receptors in fixed and circulating immunocompetent cells and activate the sympathetic and pituitary-adrenal system through similar receptors in cells that form the blood-brain interface. The latter, in turn, lead to the formation, within the brain, of proinflammatory cytokines including interleukin (IL)-1alpha, IL-1beta, IL-6, tumor necrosis factor alpha (TNF-alpha), and one or more antinflammatory cytokines including tumor growth factor beta (TGF-beta), and IL-10. Although the full panoply of central cytokines can be activated after systemic exposure, direct introduction of IL-1beta into the brain exerts a unique pattern of peripheral immune responses attributable to the special properties of reactive cells within the brain and to the "reservoir" function of the cerebrospinal fluid compartment. De Simoni et al. were the first to show that the intracerebroventricular (icv) injection of IL-1beta in rats induced a dramatic increase in the concentration of circulating IL-6 that was much greater and more prolonged than that induced by intravenous bolus injection of the same dose of cytokine. The work reported in this paper shows that the "De Simoni paradox" is mainly due to the prolonged release of the injected IL-1beta from brain to blood: a large proportion is not degraded (86%), transport out is both active and passive, and the initial exposure to IL-1beta sensitizes peripheral responses to the continuing exposure to the cytokine. Although IL-6, TNF-alpha and LPS are passively transferred from brain to blood (as shown by radioiodine-labeled tracer studies) peripheral cytokine responses to central injection differ from responses to IL-1beta. Peripheral responses to central TNF-alpha are similar to those after peripheral administration because TNF-alpha has no peripheral sensitizing effect. Peripheral response to central LPS exposure is much less than that which occurs when an amount identical with that transferred from brain to blood is administered peripherally. This is due to the fact that intracerebral injection of LPS suppresses response to peripherally administered endotoxin. Since the effect can still be demonstrated in adrenalectomized animals maintained on a constant dose of corticosterone, the brain has the capacity by as yet undefined mechanisms to suppress peripheral inflammatory responses.

Parathyroid hormone-related protein (PTHrP) induction in reactive astrocytes following brain injury: a possible mediator of CNS inflammation.

PTHrP, a peptide induced in parenchymal organs during endotoxemia and in the synovium in rheumatoid arthritis, has recently been shown to be expressed in immature or transformed human astrocytes, but not in normal cells. This finding has led us to postulate that PTHrP might also be induced in reactive astrocytes in inflamed brain and, thus, act as a mediator of CNS inflammation. To test this hypothesis, PTHrP expression was examined following cortical stab wound injury in rats, a classical model of reactive gliosis. To determine whether PTHrP was induced in glia by TNF-alpha, a known mediator of inflammation in brain and of PTHrP induction in peripheral tissues, and to determine whether PTHrP, in turn, mediated inflammatory changes in glia, in vitro studies with rat astrocytes and glial-enriched mixed brain cells were also undertaken. Consistent with previous reports of PTHrP expression in normal brain, neurons were the primary site of immunoreactive PTHrP expression in the injured cortex 1 day after stab wound injury. Over the subsequent 3 days, specific immunostaining for PTHrP and for GFAP, a marker of reactive astrocytes, appeared in reactive astrocytes at the wound edge and in perivascular astrocytes, reaching a maximum level of expression at the last time point examined (day 4). TNF-alpha induced PTHrP expression in astrocyte and glial-enriched brain cells in vitro, suggesting that this pro-inflammatory peptide was a possible mediator of PTHrP expression in CNS inflammation. PTHrP(1-34) acted in an additive fashion with TNF-alpha to induced astrocyte expression of IL-6, a cytokine with demonstrated neuroprotective effects. Astrocyte proliferation was inhibited by PTHrP(1-34) and PTHrP(1-141), acting via a PTH/PTHrP receptor cAMP signaling pathway. These studies suggest that PTHrP, analogous to its regulatory functions in other non-CNS models of inflammation, may be an important mediator of the inflammatory response in brain.

Community-acquired pneumonia--which patients are hospitalised?

BACKGROUND AND OBJECTIVE: Patients with community-acquired pneumonia can be allocated into low and high-risk mortality groups by simple clinical criteria. We studied the value of the stratification for outcome as proposed by Fine, et al. to guide the decision for in-hospital versus outpatient treatment in the emergency department. PATIENTS AND METHODS: We studied demographic data, risk group stratification and decision-making for in-hospital versus outpatient treatment in 101 consecutive medical emergency department patients with community-acquired pneumonia. We also analysed predictive factors for hospitalisation of low-risk patients. We obtained complete 30 day follow-up information. RESULTS: Forty-three of 44 high-risk patients were hospitalised after medical emergency department triage. Twenty-seven (47%) of 57 low-risk patients were hospitalised as well. Based on routine clinical assessment, hospitalisation of low-risk patients was required for poor medical condition or severe pneumonia (67%), for lack of social support (15%) and for relevant comorbidity (18%). In an univariate analysis, age (p = 0.003), C-reactive protein (p = 0.0006), presence of comorbidity (p = 0.0001), Charlson index (p = 0.0001) and active oral steroid treatment (p = 0.028) were significantly correlated with hospitalisation of low-risk patients. The 30-day mortality rate was 32% in patients allocated to the high-risk group at the time of diagnosis in the emergency department, compared to 0% in low-risk patients. CONCLUSION: Simple clinical criteria distinguish well between low and high 30-day-mortality risk in patients diagnosed with community-acquired pneumonia. Nevertheless, 47% of low-risk patients require in-hospital treatment. Age, C-reactive protein, presence of comorbidity and steroid treatment are significantly correlated with hospitalisation of low-risk patients with community-acquired pneumonia.

Blood interleukin-6 and tumor necrosis factor-alpha elevation after intracerebroventricular injection of Escherichia coli endotoxin in the rat is determined by two opposing factors: peripheral induction by LPS transferred from brain to blood and inhibition of peripheral response by a brain-mediated mechanism.

Following intracerebroventricular injection of LPS in rats, IL-6 and TNF-alpha appear in peripheral blood. To determine whether these changes are mediated by passage of the injected LPS from the brain to the blood, the time course of appearance in blood of bioactive LPS after intracerebroventricular injection was compared with the time course of appearance of IL-6 and of TNF-alpha in blood. Bioactive LPS was detected 30 min after intracerebroventricular injection, the first time interval tested. TNF-alpha appeared in peripheral blood at 30 min, IL-6 at 60 min and both cytokines as well as LPS achieved highest levels at 120 min. To determine pharmacokinetics of LPS transfer from brain to blood more precisely, radioiodinated LPS was injected intracerebroventricularly. (125)I-LPS was detected in blood as early as 5 min after intracerebroventricular injection, reached peak levels at about 2 h, and was transferred from brain to blood at a rate corresponding to bulk flow (% of brain content per min was 1.40 +/- 0.58 and 1.00 +/- 0.21% in series 1 and 2, respectively). 70.0% of total injected LPS had entered blood by 4 h. However, when administered intravenously (by a programmed pump) at the same rate that it enters the blood after intracerebroventricular injection LPS induced a much greater cytokine response than when given intracerebroventricularly. This paradoxical response was shown in further studies to be due to the simultaneous central inhibitory effect of LPS; coinjection of intracerebroventricular LPS markedly reduced the peripheral cytokine response to intravenous LPS infusion.

Blood to brain transfer of leptin in normal and interleukin-1beta-treated male rats.

To test the hypothesis that leptin was secreted from the brain into the blood of the rat, its concentration was measured in the superior sagittal sinus (SSS; which drains the cerebral cortex) and aortic blood of normal fasting male rats and rats that had been treated with iv or intracerebroventricular (icv) injections of interleukin-1beta (IL-1beta; 100 ng), a cytokine previously shown to induce peripheral leptin secretion. Plasma levels of leptin in SSS were slightly, but significantly, less than those in the aorta in control, saline-injected rats (0.99+/-0.07 vs. 1.19+/-0.10 ng/ml; n = 15; P = 0.03) and in rats injected with human IL-1beta iv (1.56+/-0.12 vs. 1.92+/-0.15 ng/ml; n = 23; P = 0.004) or icv (1.38+/-0.11 vs. 1.57+/-0.12 ng/ml; n = 23; P = 0.008). IL-1beta by either the iv or icv route significantly increased leptin levels in the aorta [1.19+/-0.10 vs. 1.92+/-0.15 ng/ml (P = 0.0002) and 1.19+/-0.10 vs. 1.57+/-0.12 ng/ml (P = 0.022), respectively]. SSS levels of leptin were also raised after iv or icv injection (P = 0.0002 and P = 0.0053, respectively). These findings demonstrate a net uptake of leptin by the cerebral cortex from peripheral blood in both normal and IL-1beta-treated animals and show that peripheral blood levels of leptin are increased by IL-1beta whether administered icv or iv.

Cells containing immunoreactive estrogen receptor-alpha in the human basal forebrain.

The distribution of estrogen receptor protein-alpha (ER-alpha)-containing cells in the human hypothalamus and adjacent regions was studied using a monoclonal antibody (H222) raised against ER-alpha derived from MCF-7 human breast cancer cells. Reaction product was found in restricted populations of neurons and astrocyte-like cells. Neurons immunoreactive for ER-alpha were diffusely distributed within the basal forebrain and preoptic area, infundibular region, central hypothalamus, basal ganglia and amygdala. Immunoreactive astrocyte-like cells were noted within specific brain regions, including the lamina terminalis and subependymal peri-third-ventricular region. These data are consistent with the location of estrogen receptors in the basal forebrain of other species and the known effects of estrogens on the cellular functions of both neurons and supporting elements within the human hypothalamus and basal forebrain.

Mechanisms by which blood levels of interleukin-6 (IL-6) are elevated after intracerebroventricular injection of IL-1beta in the rat: neural versus humoral control.

Intracerebroventricular (icv) injection of interleukin-1beta (IL-1beta) in rats induces elevated IL-6 levels in peripheral blood, exceeding those induced by iv or ip injection. Two hypotheses postulated to explain this phenomenon were tested. Mediation by peripheral sympathetic activation was excluded by showing that agents that blocked preganglionic cholinergic synapses (chlorisondamine), beta-adrenergic receptors (propanalol, butoxamine), and alpha-adrenergic receptors (phentolamine) did not prevent the IL-6 response. That the peripheral response was due to passage of the injected IL-1beta into blood from the brain was supported by several observations. Immunoreactive IL-1beta appeared in peripheral blood by 10 min after icv injection and remained constant between 10-100 min after injection; values after icv injection were virtually identical to those after iv injection at 60 and 80 min. Radioiodine-labeled IL-1beta appeared in blood as early as 5 min, and by phamacokinetic analysis was found to be transferred from the brain at a rate greater than 2% of brain content per min(-1). IL-1beta infused iv in a pattern mimicking brain to blood transfer induced IL-6 levels that were more than double the values induced by a single bolus injection and were not significantly different from the values observed after icv injection. Sustained levels of IL-1beta in blood over time contribute to the high peripheral IL-6 response. This was shown by administering the same total dose iv as a single bolus of 100 ng or in two doses of 50 ng 1 h apart. Rats given a divided dose had 6-10 times higher blood IL-6 levels at 2 h than those given a single injection. The high levels of IL-6 in blood after icv injection of IL-1beta are best explained by the reservoir function of the brain IL-1beta pool and the self-priming effect of IL-1beta in peripheral tissues.

Neuroendocrinology of infection and the innate immune system.

This chapter deals with two topics: the evolutionary and functional implications of the effects of bacterial endotoxin on the neuroendocrine system in higher vertebrates and a newly recognized neuroendocrine mechanism of immune regulation by the direct secretion of immunoregulatory cytokines from the brain. Endotoxin is a highly specific stimulus to hypothalamic-hypophysial activity; neuroendocrine responses are integrated with behavioral, body temperature, and innate immune responses. All depend upon the genetically programmed capacity of several classes of cells to distinguish molecular patterns foreign to self that are characteristic of pathogenic microorganisms. One component of the response to endotoxin and inflammation in the brain is the direct secretion into the blood (by bulk flow) of appreciable amounts of immunoregulatory cytokines that can modify peripheral levels of IL-6 and TNF-alpha. These can arise from activated glia, endothelia, choroid plexus, and possibly specific neuronal groups. Despite its being an "immune-privileged" organ, brain-presented antigens provoke a greater humoral immune response than by other routes. The capacities of the brain to regulate peripheral cytokine levels by their direct secretion into the blood and to induce antibody response are potential pathways of peripheral neuroimmunomodulation. This mechanism is integrated with the better-established modes of neuroimmunomodulation, sympathetic nervous system, and hypothalamic-pituitary axis.

[A "typical" case of pulmonary embolism]. / Ein "typischer" Fall von Lungenembolien.

A 85-year-old woman was admitted to our hospital because of a presumtive diagnosis of pulmonary thromboembolism. The patient presented with a history of progressive dyspnoea and retrosternal pain. 3-4 weeks ago she had noticed a swollen left leg. On examination a 4/6-pansystolic murmur was found. An arterial blood gas analysis showed a reduced oxygen saturation. An electrocardiogram revealed deep S-waves in lead I and pathological Q-waves in lead III. The chest X-ray showed cardiomegaly, a pulmonary nodule and an ill-defined opacity inferioposteriorly. Ventilation-perfusion mismatch was demonstrated by lung ventilation-perfusion scanning. Transthoracic echocardiography showed pulmonary hypertension and tricuspid regurgitation. On the 20th hospital day the patient died from multi organ failure. Pulmonary thromboembolism secondary to deep venous thrombosis of the lower extremities was the most likely diagnosis. In view of the patients' history of night sweat, loss of appetite and weight loss a malignant process had to be taken into consideration. A tumor originating from the right ventricle, the right ventricular outflow tract or the pulmonary artery was compatible with the clinical picture of multiple pulmonary emboli. On autopsy a polymorph cellular sarcoma measuring 6 x 3 x 3 cm was found in the right ventricular outflow tract. Section of the lung revealed a single pulmonary metastasis and multiple thromboemboli of various age. Pulmonary artery sarcomas, as described in our case, are extremely rare. The prognosis is poor and often the diagnosis is only made on autopsy.

[Progressive muscular weakness due to subacute postinfectious polyradiculitis and myelitis]. / Progrediente generalisierte Muskelschwäche bei subakuter, postinfektiöser Polyradikulitis und Myelitis.

In a 67-year-old patient, generalised stable muscular weakness preexisting for several years became rapidly progressive within a few weeks prior to hospitalisation. He died one month after admission from acute cardiocirculatory failure. There was no history of muscular pain, clinical examination showed weak or absent tendon reflexes, hyposensibility of the dorsa of his feet, fasciculations and myocloni of the muscles of the lower limbs as well as a generalised muscular atrophy. Polyneuropathy due to diabetes mellitus and monoclonal IGG-kappa-type gammopathy were preexisting. CSF examination showed inflammatory cerebral fluid changes and further investigations revealed inflammatory polyradiculopathy affecting mainly motor nerve fibres. There was evidence of a reactivated varicella-zoster infection in serum and in the cerebrospinal fluid samples. The search for a tumour, vasculitis or a drug-related cause for this syndrome remained negative. Neuropathological examination at autopsy showed subacute polyradiculitis accompanied by myelitis. The most probable cause of this disorder is immune-mediated polyradiculitis after varicella-zoster infection.

Clearance of [125I]-tumor necrosis factor-alpha from the brain into the blood after intracerebroventricular injection in rats.

To test the hypothesis that brain to blood clearance is a mechanism by which brain inflammation and damage can increase circulating acute phase cytokines, rate of transfer of [125I]-tumor necrosis factor-alpha ([125I]-TNF) from brain to blood was determined. Acid precipitable [125I]-TNF appeared in peripheral blood within 5 min of intracerebroventricular (i.c.v.) injection and was cleared from brain to blood following first order kinetics at a fractional rate of 0.01123 +/- 0.0030/min, a value virtually identical with a previously determined clearance rate of [125I]-IL-6. Area under blood concentration curve compared with that after intravenous injection shows that 31.6 +/- 5.8% of the intracerebral dose reached peripheral blood in 4 h. Elevated ratios of superior sagittal sinus to aortic blood radioactivity concentration at 1 and 3 h (1.48 +/- 0. 26, p = 0.042; 1.95 +/- 0.39, p = 0.026, respectively) indicate that TNF-alpha drains from brain at least in part via the sagittal sinus. Escherichia coli lipopolysaccharide i.c.v. injection increased the rate of brain efflux of TNF-alpha.

Alternative pathways of neural control of the immune process.

Less well established alternative neuromodulatory pathways are neuropeptide-mediated axon reflexes of sensory neurons, gut immunotrafficing, gut transmucosal transport of endogenous bacterial toxin, and the direct secretion of immunoregulatory cytokines by the brain. TNF-alpha and IL-1ra enter peripheral blood after their intracerebroventricular (i.c.v.) injection. Closed head injury or stroke increases blood IL-6 and the acute phase response; neuroblastomas immunosuppress by secreting TGF-beta. The IL-6 that appears in the blood after i.c.v. IL-1 in the rat is partly derived by secretion from the brain into the superior sagital sinus (Romero et al.; 1996. Am. J. Physiol. 270: R518) and is not dependent on peripheral sympathetic activation. Central endothelium and choroid plexus are potential sources of sagital sinus IL-6. TNF-alpha, which appears in blood after i.c.v. LPS, but not IL-1 beta, is due largely to toxin leaving the brain compartment and activating peripheral immunoreactive tissues. Antigens and cytokine immunoregulators drain into cervical lymph. Changes in glial milieu induced by intrinsic neuronal activity could by secretion from brain to blood modulate peripheral immunoreactivity.

The relationship between growth hormone kinetics and sarcopenia in postmenopausal women: the role of fat mass and leptin.

Sarcopenia, the decline in body cell mass (BCM) and especially in muscle mass with age, is an important age-related cause of frailty and loss of independence in the elderly. Because the decline in BCM with age parallels a decline in GH secretion from young adulthood to old age, loss of GH secretion has been considered an important contributory cause of sarcopenia in the elderly. To test this hypothesis in a group of healthy postmenopausal women (n = 15; mean +/- SD age, 66.9 +/- 7.8 yr), 24-h GH concentrations and secretory kinetics were correlated with BCM (measured by whole body counting of 40K) and percent body fat (measured by dual energy x-ray absorptiometry or neutron inelastic scattering). Serum leptin levels were determined as a measure of adipocyte mass. Contrary to prediction, GH secretion was lower in women with higher BCM (r = 0.50; P < 0.05), whereas their mean fat mass was higher (r = 0.51, P < 0.05). These data indicate that sarcopenia in postmenopausal women is not associated with reduced GH secretion and is inversely correlated with fat mass. Serum leptin levels were inversely associated with GH secretion (r = -0.67; P < 0.006). Although a causal relationship has not been demonstrated, these data suggest that leptin could modulate GH secretion through its action on the aging hypothalamic-pituitary axis, or that GH regulates leptin secretion.

[Pulmonary tuberculosis with resistance to 4 antitubercular drugs]. / Lungentuberkulose mit Resistenz gegen vier Antituberkulotika.

A 32-year-old immigrant from Pakistan was admitted to our hospital with cavernous pulmonary tuberculosis. He gave a history of several 1 to 2-months courses of antimycobacterial treatment administered earlier in Pakistan. We initiated combined therapy including isoniazid, rifampin, pyrazinamide, and ethambutol. Subsequently, results of susceptibility testing from M. tuberculosis-complex strains isolated before the onset of treatment documented the presence of resistance against both isoniazid and rifampin which may have been primary or acquired drug resistances. During the course of treatment, two additional resistances to pyrazinamide and ethambutol developed which were probably due to the initial therapy with only two active antimycobacterial agents. The emergence of multidrug-resistant strains of M. tuberculosis complex is a world-wide problem. Our case indicates that multiresistance must be considered in every patient presenting with tuberculosis. If there is a strong suspicion of multidrug-resistant tuberculosis, initial treatment with a combination of 5-6 antimycobacterial agents seems advisable until the results of susceptibility testing become available.

Changes in public psychiatric hospitalization in Oregon over the past two decades.

OBJECTIVE: In 1988 a governor's commission in Oregon recommended dramatic changes in the state's approach to public psychiatric hospitalization. To evaluate the effect of the recommendations, this study examined characteristics of hospitalization for patients with schizophrenia and bipolar disorder in public psychiatric facilities between 1981 and 1984 and between 1991 and 1994. METHODS: Patients with schizophrenia and bipolar disorder (N=621) were identified as part of a larger study that examined civil commitment in one of Oregon's state hospitals in 1986. Data on the patients' hospitalizations were obtained from a statewide computerized mental health information system. RESULTS: The legal status of hospitalized patients differed between the two time periods, with voluntary hospitalizations overrepresented in 1981-1984 and civil commitments overrepresented in 1991-1994. The locus of hospitalization varied greatly between the two time periods. All hospitalizations in 1981-1984 took place in one of Oregon's three state hospitals. In 1991-1994, subjects were hospitalized in 13 different institutions, including state and community hospitals and specially designed nonhospital inpatient facilities. CONCLUSIONS: Patterns of inpatient hospitalization for public psychiatric patients changed dramatically from 1981-1984 to 1991-1994. The extensive use of community and nonhospital facilities raises questions about monitoring of quality of care in these diverse and decentralized facilities.

Clearance of 125I-labeled interleukin-6 from brain into blood following intracerebroventricular injection in rats.

To test the hypothesis that interleukin-6 (IL-6) induced within the brain can be released into peripheral blood, 125I-labeled IL-6 was injected into the lateral cerebral ventricle of rats, and its concentration in peripheral blood followed serially. Acid-precipitable tracer appeared within 5 min of injection and entered the blood following first-order kinetics (fractional rate, 0.0116 +/- 0.0022/min). Comparison of areas under the curve of intracerebroventricular (icv) vs. iv injection showed that 37.1-46.5% of tracer injected into the lateral cerebral ventricle appeared in the blood over a 4-h period. icv IL-6 exits at least in part via venous drainage (superior sagittal sinus/aortic concentration gradient was 1.47 +/- 0.23 and 3.05 +/- 0.87 in two separate groups). Prior icv injection of human IL-1beta (100 ng) did not alter rate of degradation or of exit ofradioiodine-labeled IL-6 from the brain. These studies indicate that a relatively high proportion of IL-6 that arises in the brain enters the peripheral circulation. Direct secretion of IL-6 from brain to blood may be a mechanism by which the brain modifies peripheral metabolic, endocrine, and immune activity.

Interleukin-6 (IL-6) is secreted from the brain after intracerebroventricular injection of IL-1 beta in rats.

To test the hypothesis that the brain is a source of the interleukin-6 (IL-6) that appears in the peripheral circulation of rats after intracerebroventricular (icv) injection of IL-1 beta, the concentration of bioactive IL-6 in superior sagittal sinus (SSS) blood plasma was compared with aortic plasma 4 h after icv injection of 100 ng of recombinant human IL-1 beta at a time at which cerebrospinal fluid (CSF) IL-6 concentration was found to be markedly elevated. In three separate experiments, CSF IL-6 concentration (pg/ml; values are means +/- SE) was significantly elevated after icv IL-1 beta compared with saline control injections (25,879 +/- 11,472 vs. 35.5 +/- 5; 32,323 +/- 4,945 vs. 128 +/- 29; 114,410 +/- 33,563 vs. 848 +/- 250, respectively). The concentration of plasma IL-6 (pg/ml) in the aortas of rats injected intracerebroventricularly with IL-1 was greater than in controls [252 +/- 93 vs. 36.7 +/- 8.3, P = 0.0037; 361 +/- 95 vs. 57 +/- 13, P = 0.02; 2,254 +/- 550 vs. 1,239 +/- 666, P = 0.26 (NS)]. In IL-1-injected animals, SSS venous plasma IL-6 (pg/ml) was greater than in the aorta in all three studies (1,617 +/- 357 vs. 252 +/- 93, P = 0.0011; 3,754 +/- 1,188 vs. 361 +/- 95, P = 0.024; 8,208 +/- 1,388 vs. 2,254 +/- 550, P = 0.0054). The concentration difference (pg/ml) between SSS and aorta was significantly greater after IL-1 beta injection than in diluent-injected animals (1,365 +/- 369 vs. 48.3 +/- 13, P = 0.0083; 3,393 +/- 1,203 vs. 126 +/- 59, P = 0.035; 5,954 +/- 1,260 vs. 494 +/- 774, P = 0.0042). Suppression of peripheral sympathetic activation by preganglionic cholinergic blockade (chlorisondamine, 250 micrograms sc) did not prevent the usual IL-1-induced elevation in aortic blood IL-6 (3,272 +/- 1,174 vs. 244 +/- 74 pg/ml, P = 0.0012) nor the increased SSS-aortic gradient (2,541 +/- 1,134 vs. 165 +/- 48, P = 0.0142 by Mann-Whitney comparison). Injection of rat/human corticotropin-releasing hormone (CRH; 10.0 micrograms) icv did not change IL-6 concentration in CSF or in peripheral blood. These studies demonstrated that the brain and/or its supporting structures are activated by icv IL-1 beta to release IL-6 into the blood and that the effect is not dependent on peripheral sympathetic activity or central mobilization of CRH. Direct secretion of IL-6 and possibly of other cytokines from the brain is postulated to be a pathway of neuroimmunomodulation.