Psychotherapy and Neuroscience

Inflammatory v.s. Antiinflammatory Protein Expression

During completed HPA expression, simultaneous activation and release of norepinephrine by locus coeruleus and brainstem alpha and beta adrenergic receptors and epinephrine in the adrenal medulla stimulate peripheral sympathetic nervous system neurons (SNS) (Elenkov et al., 2000). The SNS increases heart rate, skin conductance (sweating), diastolic and systolic blood pressure, respiration, etc. during stress. Epinephrine and norepinephrine through alpha-adrenoreceptors (α1ARs and α2ARs) and beta-adrenoreceptors (β1ARs, β2ARs, β3ARs) bind to proteins in the peripheral nervous system. This stimulates the expression of transfer factors that allows for the expression of humoral immunity or T helper 2 (Th2) cytokines, such as interleukin (IL) IL-4, IL-5, IL-10, IL-13, TGF-β (Elenkov et al., 1999, 2000). Increased hypothalamic-pituitary-adrenal axis activation manifested in increased glucocorticoid secretion and respective GR expression also stimulates the expression for humoral immunity and Th2 cytokine expression. Increased HPA axis activity is evidenced during states of acute stress, chronic active alcoholism, long-term excessive exercise, and during pregnancy’s last trimester, and in conditions of Cushing’s syndrome and melancholic depression (Elenkov et al., 1999). Depression is also accompanied by proinflammatory cytokine IL-6 activation (Kiecolt-Glaser & Glaser, 2002). Repeated and chronic inflammation relating to viral infection can be accompanied by a shift from immunity to Th2 dominance, which suppresses immunity and increases the likelihood for the development of superinfection. Serious injury, which initially stimulates proinflammatory cytokines at the wound site, can later cause a shift to Th2 anti-inflammatory dominance in response to the need for anti-inflammatory response and IL-10 secretion. This results in suppressed wound immunity and subjects the site to post-infectious complications. Tumor growth is reflective of suppressed immunity and a deficit in proinflammatory cytokines at a tumor site along with a local overproduction of IL-10 and TGF-β (Elenkov et al., 2000).

When central HPA and norepinephrine and epinephrine levels aren’t able to mount significant sympathetic arousal, the titer shifts to suppress Th2 dominance for T helper 1 (Th1) dominance. Th1 cytokines for cellular immunity are proinflammatory cytokines, e.g. interleukin (IL) IL-2, IL-12, IFN-γ, TNF-αβ (Elenkov et al., 1999), IL-6, IL-8 (Imrich, 2002), and IL-1α and β (Kiecolt-Glaser & Glaser, 2002) that when activated fight infection by mediating inflammatory processes. Central inflammatory states are evidenced during adrenal insufficiency, chronic stress, atypical or seasonal depression, posttraumatic stress disorder, nicotine withdrawal, chronic fatigue syndrome, postpartum period of pregnancy, etc (Webster et al., 1998). Th1 predominance enhances immunity but also increases susceptibility for peripheral involvement and autoimmune-inflammatory disease. It is evidenced in conditions presenting site-specific symptoms of rheumatoid arthritis, multiple sclerosis, auto-immune thyroid disease, and type 1 diabetes mellitus along with a proinflammatory shift to IL-12, TNF-α, IFN-γ and a deficit in IL-10 secretion (Elenkov et al., 2000).

On a molecular level many Th1 cytokines are permitted expression with the activation of transfer factors, such as AP-1 and NF-κB (nuclear factor-kappa B) (Liz-Grana et al., 2001). The most prominent, NF-κB, is a heterodimer that consists of two proteins, p65 (also called RelA) and p50. In its quiescent state NF-κB is found in the cytoplasm bound to two proteins, IκBα and IκBβ (Inhibitor kappa B alpha and beta) that prevent it from translocating to the cell’s nucleus for gene expression (Barnes & Karin, 1997). Many proteins are able to activate and bind to NF-κB, including cell surface proteins like TRAF2 and TRAF6 for cytokines TNF-α and IL-1 respectively (Maniatis, 1997; Qi & Pekala, 2000) as well as stress-induced activators like protein kinase C (PRC), mitogen activated protein kinase (MAPK), viruses, and oxidants (Barnes & Karin, 1997; Lallena et al., 1999). For instance both TRAFs interact with enzymes that mediate cellular activity and is activated in response to cellular stressors, mitogen activating protein kinase/extracellular signal-regulated kinase kinase kinase and mitogen activating protein 3 kinases (MEK kinase and MAPKKK) (Hirano et al., 1996; Garrington & Johnson, 1999). Both form a complex called nuclear inhibiting kinase (NIK), that releases IκB’s ability from inhibiting NF-κB. IκB’s repression allows for its expression NF-κB (Maniatis, 1997; Qi & Pekala, 2000). NIK’s activation is either independent of (Mercurio et al., 1997), is required for during in vitro activation of (Chen et al., 1999), or in interaction with (Woronicz et al., 1997) other proteins, IKKα or IKK1 and IKKβ or IKK2, (Maniatis, 1997). Their interaction mediates the sequential phosphorylation, ubiquitination, and degradation of the IκB complex that allows for NFκB’s activation and expression. IKKα and IKKβ activate NFκB by phosphorylating IκBa’s two serine residues Ser 32 and Ser 36 and IκBβ’s serines 19 and 23, respectively (Roff et al., 1996; Woronicz et al., 1997; Zandi & Karin, 1999). IKK mediated degradation and phosphorylation of IκBα is associated with transient NF-κB activation, whereas IKK mediated phosphorylation of IκBβ is involved in its sustained activation (Tak & Firestein, 2001). In summary IκB’s sequential phosphorylation, ubiquitination, and degradation allows for proinflammatory NF-κB’s release from the cytoplasm, translocation to the nucleus, and ultimate binding to specific DNA sequences for full expression of respective proinflammatory cytokines (e.g. TNF-α, IL-1, and IL-6), chemkines, enzymes that mediate inflammatory states, etc (Chikanza, 2002; Elenkov et al, 2000; O’Connor et al., 2000). Disruption in IκB inhibitory influence, particularly IκBβ noted above, results in prolonged activation of NF-κB in response to inflammatory stimulation.

NF-κB activity that mediates proinflammatory cytokine gene transcription, e.g. IL-1, also plays an important role in regulating glucocorticoid receptor gene transcription (de Kloet et al., 1998; Pariante et al., 1999) and vice versa. Fully functional GRs that bind GCs interfere in transfer factor (e.g. TRAFS) related proinflammatory cytokine gene transcription of IL-1β and TNF-α by strengthening IκBα’s ability to bind, inhibit, and return NF-κB to the cytoplasm (Barnes & Karin, 1997; Angeli et al., 1999). Glucocorticoids inhibit NF-κB expression and gene transcription by functional interfering and repressing NFκB’s p65 expression (De Bosscher et al., 2000). This is probably mediated by IκB’s inhibitory influence noted above. This accounts for GCs’anti-inflammatory actions (de Kloet et al., 1998; Wissink et al., 1998). IL-10 also inhibits the proinflammatory transcription of NF-κB and the degradation of IκB by IKK by increasing nuclear levels of its inhibitor IκB (Schottelius et al., 1999; Asadullah et al., 2003). Again, inflammatory actions not only facilitate NF-κB’s return to the cytoplasm but also allows for nuclear translocation and gene transcription of the anti-inflammatory mechanism, which seeks to inhibit the inflammatory process.

Proinflammatory and anti-inflammatory cytokines complement the secretion of one another and produce various cytokine cascades. Both circulating glucocorticoids and epinephrine-norepinephrine (through beta adrenergic receptors) regulate the secretion of proinflammatory cytokines. Elenkov & Chrousos (2002) note that glucocorticoid secretion directly inhibits the secretion of cytokines IL-12 and tumour necrosis factor-alpha (TNF-α) by interfering in their respective transcription factors (noted above). This action concurrently inhibits the secretion of proinflammatory cytokines IL-2 and interferon-gamma (IFN-γ) through GC mediated secretion of anti-inflammatory T-helper cytokines IL-4 and IL-10 (Fiorentino et al., 1991; de Waal Malefyt et al., 1993). Catecholamines inhibit the secretion of IL-12 and TNF-α and directly stimulate IL-10, which serves to regulate proinflammatory secretion of IL-2 and IFN-γ. Cathecholamines concurrently indirectly suppress IL-1 by IL-10’s inhibiting effect on TNF-α (Elenkov et al., 2000). Both glucocorticoids and catecholamines regulate the cascade for production of proinflammatory cytokines (through mechanisms noted above). Proinflammatory cytokines can also influence and enhance negative feedback capabilities of HPA. During inflammation IL-1β that has been synthesized by the hypothalamus’ PVN, can then directly stimulate pituitary cells to secrete ACTH (Licinio & Wong, 1997). IL-6 also plays an important role in augmenting the secretion of GCs, with IL-1α playing a stimulatory role in involving IL-6 in the shift toward anti-inflammation (Miller et al., 1999). The end product of the HPA, GC secretion suppresses the production of IL-6 and IL-1β (Chrousos, 1995).

Each cytokine is associated with characterized behaviors. For instance IL-6 is associated with fatigue (Swain, 2000). Interferon alpha (IFN-α) mediates its effects and characterizes senses of anhedonia and depression, which can be reversed by antidepressant therapy (Yamano et al., 2000; Sammut et al., 2002). IL-1α and IL-1β, IL-6, and TNF-α are all associated with sickness behaviors (Konsman et al., 2002) evidenced in decreases in general activity, exploratory behaviors, social and sexual behaviors, food and water intake, and body care needs as well as impaired learning and memory (Danzer, 2001). Injections of IL-1, that increase the expression and availability of circulating IL-1, induce sickness behaviors of fever, anorexia, increases in slow-wave sleep, alterations in neuroendocrine and HPA activity, and the induction of neurodegeneration and cell death (Rothwell, 1999).

In response to infection-related stress proinflammatory cytokines, TNF-α, IL-1, and IL-6, are released in a cascade-like fashion. Both TNF-α and IL-1 stimulate the central secretion of IL-6 (Chrousos, 1995; Takahashi et al, 1995). TNF mediated increases in IL-6 gene expression is dependent on the p38 mitogen-activated protein kinase (MAPK) activation of NF-κB’s p65 (Vanden Berghe et al., 1998). IL-6 stimulates hypothalamic CRH and vasopressin (AVP) release above the level of the median eminence (Navarra et al., 1990; Harbuz et al., 1992; Spinedi et al., 1992), which in turn stimulates ACTH and prolactin release in the anterior and posterior pituitary (Chrousos, 1995; Ray & Melmed, 1997) respectively. IL-6’s pituitary expression and input eventually stimulates steroid production and secretion in the adrenal cortex (Path et al., 1997). In addition TNF activation results in elevated corticosterone levels with the lowest dose having a maximal effect (Takahashi et al., 1995). The above is illustrative of the role of proinflammatory cytokines in indirectly stimulating HPA activity. This is the way the body can exert influence on the mind for sickness behavior.

Local CRH and substance P secretion and expression directly stimulates IL-1 and IL-6 and TNF-α and IL-12, respectively (Elenkov & Chrousos, 2002). Cytokine proinflammatory-induced release of corticotropin releasing hormone (CRH) has a central anti-inflammatory effect through its influence on the HPA neurohormone cascade for adrenocortical secretion of glucocorticoids and a proinflammatory effect on peripheral inflammatory sites (Friedman & Irwin, 1995; Kapcala et al., 1995; Webster et al., 1998). Furthermore, endogenous cortisol (DEX) administration causes decreases in IL-6, TNF-α, and serum TNF receptor p75 plasma levels but does not alter plasma IL-10 levels and TNF receptor p55 plasma levels (Schuld et al., 2001). This is suggestive that the HPA’s initial products locally can stimulate proinflammatory secretion and its final by-product of adrenocortical cortisol secretion has a modulatory affect on proinflammatory response.

Stress seems to play a role in stimulating proinflammatory cytokine secretion. Immobilization stress in laboratory animals causes peripheral CRH mediated increases in plasma IL-6 and ACTH levels (Ando et al., 1998) and increases in 30 minute TNF-α convertase (TACE) activity and one hour TNF-a levels in the cortex after the onset of stress (Madrigal et al., 2002). Localization of Fos protein (Rivest & Rivier, 1994) during either footshock stress or IL-1β injection produces CRH-immunoreactivity on the same hypothalamic PVN parvocellular (PVNpc) neurons. In addition, footshock stress also produces increases in serum corticosterone and IL-6 secretion and suppresses lymphocyte mitogenic activity in the Fischer F344 rat (Kusnecov et al., 1995). Multiple mild to moderate stressors (e.g. aversive auditory tone, restraint and metabolic stressors) fail to stimulate corticosterone secretion in IL-1r knock-out (IL-rKO) mice, suggesting that IL-1r proinflammatory cytokine has a contributory role in regulating psychological-stress by inducing HPA activity (Goshen et al., 2003).

In summary, during psychological stress the central secretion of proinflammatory cytokines serves to enhance and further stimulate the anti-inflammatory effects of stress-induced HPA activity. Both proinflammatory and anti-inflammatory cytokines have the capacity to stimulate and further deepen HPA axis activity via CRH and glucocorticoids, respectively. How HPA neurohormones and neuroimmune cytokines interact with one another in stress induction will be examined in succeeding sections 1.44-1.49.


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