Raf De Jongh

Elevated serum interleukin-6 (IL-6) and IL-6 receptor concentrations in posttraumatic stress disorder following accidental man-made traumatic events

BACKGROUND Recently, it has been reported that serum interleukin-1 beta (IL-1 beta), but not soluble IL-2 receptor (sIL-2R), concentrations were significantly higher in patients with posttraumatic stress disorder (PTSD) than in normal volunteers, and that psychological stress in humans is associated with increased secretion of proinflammatory cytokines, such as IL-6. METHODS The aim of the present study was to examine the inflammatory response system in patients with PTSD through measurements of serum IL-6, sIL-6R, sgp130 (the IL-6 signal transducing protein), sIL-1R antagonist (sIL-1RA; an endogenous IL-1 receptor antagonist), CC16 (an endogenous anticytokine), and sCD8 (the T suppressor-cytotoxic antigen). RESULTS Serum IL-6 and sIL-6R, but not sgp130, sIL-RA, CC16, or sCD8, concentrations were significantly higher in PTSD patients than in normal volunteers. Serum sIL-6R concentrations were significantly higher in PTSD patients with concurrent major depression than in PTSD patients without major depression and normal volunteers. There were no significant relationships between serum IL-6 or sIL-6R and severity measures of PTSD. CONCLUSIONS The results suggest that PTSD is associated with increased IL-6 signaling. It is hypothesized that stress-induced secretion of proinflammatory cytokines is involved in the catecholaminergic modulation of anxiety reactions.

Negative Immunoregulatory Effects of Antidepressants: Inhibition of Interferon-γ and Stimulation of Interleukin-10 Secretion

There is now some evidence that major depression is accompanied by activation of the inflammatory response system. There is also some evidence that antidepressants may suppress the release of cytokines, such as interleukin-1β (IL-1β) and IL-6 by activated monocytes and IL-2 and interferon-γ (IFNγ) by activated T cells. This study was carried out to examine the effects of clomipramine, sertraline, and trazodone on the stimulated production of IFNγ, a pro-inflammatory cytokine, and IL-10, a negative immunoregulatory cytokine. Whole blood of nine healthy volunteers was stimulated with PHA, 5 μg/mL and LPS, 25 μg/mL for 72 hr with and without incubation with clomipramine, 10−6 and 10−9 M, sertraline, 10−6 and 10−8 M, and trazodone, 10−6 and 10−8 M. All three antidepressants significantly reduced IFNγ secretion, whereas clomipramine and sertraline significantly increased IL-10 secretion in culture supernatant. All three antidepressants significantly reduced the IFNγ/IL-10 ratio. The results suggest that antidepressants, at concentrations in the therapeutical range, have negative immunoregulatory effects through inhibition of IFNγ and stimulation of IL-10 release.

The inflammatory response system and the availability of plasma tryptophan in patients with primary sleep disorders and major depression

BACKGROUND It is now well established that major depression is accompanied by an immune-inflammatory system response and that indicators of the latter are inversely correlated with lower availability of plasma tryptophan in depression. Inflammation and infection can alter sleep architecture, whereas sleep disturbances can impair immune functions. AIMS AND METHODS The aims of the present study were to examine: (i) immune-inflammatory markers, i.e. serum interleukin-6 (IL-6), IL-8, IL-6 receptor (IL-6R), IL-1R antagonist (IL-1RA), gp130, and prostaglandin E2 (PGE2) production by mitogen-stimulated whole blood and the availability of plasma tryptophan in patients with primary sleep disorders, major depression and healthy volunteers; and (ii) the relationships between the availability of tryptophan and indicators of the immune-inflammatory response system. RESULTS Mitogen-stimulated release of PGE2, and serum IL-6 and IL-8, were significantly increased in both depressed and sleep disordered patients compared to normal controls. Serum IL-1RA was significantly higher in depressed patients than in normal controls. Patients with depression and sleep disorders had a significantly lower availability of tryptophan than normal controls. There were significant and inverse relationships between the availability of plasma tryptophan and serum IL-1RA, IL-6 and IL-8. CONCLUSIONS The results suggest that (i) there is an activation of the immune-inflammatory response system in primary sleep disorders and depression; and (ii) the decreased availability of plasma tryptophan may be related to the inflammatory system response.

The immune-inflammatory pathophysiology of fibromyalgia: increased serum soluble gp130, the common signal transducer protein of various neurotrophic cytokines

Fibromyalgia is a chronic, painful musculoskeletal disorder characterized by widespread pain, pressure hyperalgesia, morning stiffness and by an increased incidence of depressive symptoms. The etiology, however, has remained elusive. The aim of the present study was to examine the inflammatory response system (IRS) in fibromyalgia. Serum interleukin-6 (IL-6), soluble IL-6 receptor (sIL-6R), sgp130, sIL-1R antagonist (IL-1RA) and sCD8 were determined in 33 healthy volunteers and in 21 fibromyalgia patients, classified according to the American College of Rheumatology criteria. Severity of illness was measured with several pain scales, dolorimetry and the Hamilton Depression Rating Scale (HDRS). Serum sgp130 was significantly higher and serum sCD8 significantly lower in fibromyalgia patients than in healthy volunteers. Serum sIL-6R and sIL-1RA were significantly higher in fibromyalgia patients with an increased HDRS score (> or = 16) than in normal volunteers and fibromyalgia patients with a HDRS score < 16. In fibromyalgia patients, an important part of the variance in sCD8 (50.3%) and IL-1RA (19.3%) could be explained by the HDRS score; 74.3% of the variance in sIL-6R was explained by the combined effects of pain symptoms and the HDRS score; and 25.9% of the variance in serum sgp130 was explained by stiffness. The results support the contention that pain and stiffness in fibromyalgia may be accompanied by a suppression of some aspects of the IRS and that the presence of clinically significant depressive symptoms in fibromyalgia is associated with some signs of IRS activation.

Immune activation in the early puerperium is related to postpartum anxiety and depressive symptoms

The pathophysiology of the postpartum blues, common transient mood disorders in the first week postpartum, has remained elusive. Recently, however, it has been shown that depression and anxiety disorders are accompanied by activation of the inflammatory response system (IRS). This study was developed to determine whether the postnatal blues is associated with IRS activation. Serum concentrations of interleukin-6 (IL-6), IL-6 receptor (IL-6R), gp130 (the IL-6 signaling protein), IL-1R antagonist (IL-1RA) and leukemia inhibitory factor receptor (LIFR) were assayed in 22 nonpregnant women and in 91 pregnant women before delivery and 1 and 3 days after delivery. On each occasion the parturient women completed the State version of the Spielberger State-Trait-Anxiety-Inventory (STAI) and the Zung Depression Rating Scale (ZDS). Serum IL-6, IL-1RA and LIFR were significantly higher in pregnant women at the end of term than in nonpregnant women.

The inflammatory response following delivery is amplified in women who previously suffered from major depression, suggesting that major depression is accompanied by a sensitization of the inflammatory response system

BACKGROUND There is now evidence that some patients with major depression show an activation of the inflammatory response system (IRS). This study was carried out to examine whether major depression may induce sensitization with increased IRS responses to the stress of child birth. METHODS Serum concentrations of interleukin-6 (IL-6), the soluble IL-6 receptor (sIL-6R), sgp130 (the IL-6 signal transducing protein) and the sIL-1R antagonist (sIL-1RA) were determined in 16 and 50 women with and without a lifetime history of major depression, respectively. Blood was collected 3-6 days before delivery and 1 and 3 days after delivery. On each occasion the women completed the Zung Depression Rating Scale (ZDS). RESULTS Serum IL-6, sIL-6R, sIL-1RA were significantly higher 1 and 3 days after delivery than before. Women who had suffered from a lifetime history of major depression had greater increases in serum IL-6 and sIL-1RA in the early puerperium than women without a lifetime history. Women who had suffered from a lifetime history of major depression had significantly higher IL-6, and sIL-1RA concentrations 1 and 3 days after delivery than women with a negative life-time history. CONCLUSIONS The responses of IL-6 and sIL-1RA following delivery are amplified in women who previously suffered from major depression. The results suggest that major depression is accompanied by a sensitization of the IRS.

The in vitro immunosuppressive effects of moclobemide in healthy volunteers.

BACKGROUND Many studies have demonstrated that major depression is related to an activation of the inflammatory response system (IRS) with an increased production of proinflammatory cytokines. It has been shown that tricyclic antidepressants and serotonin reuptake inhibitors suppress the activation of the IRS in depression and have negative immunoregulatory effects in vitro. Little is known on the immune effects of moclobemide, a reversible monoamine oxidase A inhibitor. METHODS We examined, in nine normal volunteers, the in vitro effects of moclobemide on the production of interleukin-6 (IL-6), IL-8, tumor necrosis factor-alpha (TNFalpha), interferon-gamma (IFNgamma), IL-10 and the IL-1 receptor antagonist (IL-1RA) by diluted whole blood stimulated or not with lipopolysaccharide (LPS)+phytohemagglutinin (PHA). RESULTS Moclobemide 10(-3) and 10(-5) M significantly suppressed the unstimulated production of TNFalpha and IL-8, and significantly enhanced the stimulated-production of IL-10. The production of IL-6, IL-1RA and IFNgamma was not significantly affected either in the unstimulated or stimulated conditions. CONCLUSIONS Moclobemide has negative immunoregulatory capacities through inhibition of the production of proinflammatory cytokines, i.e. TNFalpha and IL-8, and through enhancement of the production of IL-10, an anti-inflammatory cytokine.

Interleukin-6 and perioperative thermoregulation and HPA-axis activation.

Surgery is followed by an acute-phase response, including hypothalamo-pituitary-adrenal (HPA)-axis activation and fever. Considering its physiological properties and its behaviour in plasma after stress and surgery, the pro-inflammatory cytokine interleukin (IL)-6 is a putative candidate in eliciting these stress-related symptoms. However, evidence for this hypothesis is lacking. Rats subjected to individual psychological stress for 1h were injected intraperitoneally with saline or 3.33 microg per 100g rat neutralizing antibodies against rat IL-6. Thereafter, the single-housed rats were anaesthetized for 25 min, with or without undergoing a laparotomy. Intermittently, oesophageal temperatures were measured at defined time points. A parallel group of rats undergoing the same study protocol were decapitated, at time points when body temperatures differed, to obtain blood for measurement of plasma adrenocorticotropic hormone and corticosterone. Individual housing resulted in hyperthermia. Antibodies against IL-6 accelerated normalization of body temperature after individualizing stress, limited postoperative hyperthermia after laparotomy, but accentuated hyperthermia after anaesthesia alone. Antibody administration was not able to significantly influence the plasma hormone levels during any experiment. The present study indicates that IL-6 is a thermoregulatory factor during psychological, anaesthesiological and surgical stress, but the cytokine does not participate in HPA-axis activation until 6h after anaesthesia or surgery. A dose-finding study with antibodies against IL-6 ought to further identify the degree of contribution of IL-6 to perioperative thermoregulation.

Effects of pregnancy and delivery on serum concentrations of Clara Cell Protein (CC16), an endogenous anticytokine: lower serum CC16 is related to postpartum depression

There is now some evidence that lower serum concentrations of Clara Cell Protein (CC16) are related to stress-induced anxiety, psychoses and major depression. This study was developed to determine whether serum CC16 is lowered in the early puerperium and whether Postnatal Depression and Postnatal Blues are associated with lower levels of serum CC16. Serum concentrations of CC16 were assayed in 17 non-pregnant women and in 98 pregnant women before delivery and 1 and 3 days after delivery. On each occasion the parturients completed the State version of the Spielberger State-Trait Anxiety Inventory (STAI) and the Zung Depression Rating Scale (ZDS). Serum CC16 was significantly lower in pregnant women, at the end of pregnancy as well as 1 and 3 days after delivery, than in the non-pregnant women. Serum CC16 was somewhat, although significantly, higher 1 and 3 days after delivery than before delivery. Parturients who developed a postpartum depression had significantly lower serum CC16 concentrations than women who did not. There were no significant differences in serum CC16 between the puerperal women whose STAI or ZDS scores increased in the puerperium and those whose scores did not. It is concluded that in puerperal women there is a decreased anti-inflammatory capacity in the serum, in part caused by lowered serum CC16, and that the latter may be related to the development of postpartum depression.

Serotonin-immune interactions in detoxified chronic alcoholic patients without apparent liver disease: activation of the inflammatory response system and lower plasma total tryptophan

The aims of the present study were to examine (1) the inflammatory response system (IRS), through measurements of serum interleukin-6 (IL-6), soluble IL-6 receptor (sIL-6R), sgp130 (the soluble form of the IL-6 transducer signal protein), CC16 (Clara Cell protein; an endogenous anti-cytokine), IL-1R antagonist (IL-1RA), IL-8 and sCD14; and (2) the availability of plasma total tryptophan to the brain in chronic alcoholic patients without apparent liver disease (AWLD). Detoxified AWLD patients had significantly lower plasma tryptophan and serum CC16 and significantly higher serum IL-1RA and IL-8 concentrations than normal volunteers. There were significant correlations between the availability of tryptophan to the brain and serum IL-6, IL-8 and IL-1RA (all negative) and CC16 (positive). The results suggest that (1) there is, in detoxified AWLD patients, an activation of the monocytic arm of cell-mediated immunity and a lowered anti-inflammatory capacity of the serum; and that (2) lower availability of plasma tryptophan to the brain in detoxified AWLD patients is related to activation of the IRS. Lower CC16 may be one factor predisposing chronic alcoholic patients toward infectious disorders.