Immuneinduced Longlasting Changes In The Hpa System

Let us consider the changes in the biological substrate that may underlie such long-lasting cross-sensitization. Because largely different brain circuits are involved in the activation of the HPA system by immune and emotional stressors (Sawchenko, Brown, Chan, Ericsson, Li, Roland, & Kovacs, 1996), it was obvious to search for functional alterations within the HPA system rather than in stressor-responsive neural projections to the PVN. So far, long lasting alterations have been found at the level of the hypothalamic CRH neurons, of the pituitary gland and in feedback mechanisms. Before going into details of these changes it should be noted that single immune activation induces little or no long-term alterations in the resting levels of ACTH and corticosterone in the blood or the content of these hormones in the pituitary gland and adrenal gland respectively. Therefore, immune induced sensitization of the HPA system appears to be associated with altered responsivity rather than with altered resting activity of the HPA system.

Corticotropin Releasing Hormone (CRH) producing neurons situated in the parvocellular part of the paraventricular nucleus (PVN), are activated by IL-1 and play a crucial role in IL-1 induced ACTH and corticosterone secretion (Berkenbosch, Van Oers, Del Rey,Tilders, & Besedovsky, 1987; Rivest 1995; Ericsson et al., 1995; Gaykema et al., 1995). In collaboration with Aguilera's group in Bethesda, we found that 1-2 weeks after IL-1 priming, CRH neurons showed little or no changes in the expression levels of CRH mRNA, CRH peptide stores and CRH turnover (Schmidt et al., 1995a; Tilders et al., in prep). Another peptide that plays a prominent role in the control of ACTH secretion is vasopressin (AVP), which strongly potentiates the ACTH releasing effect of CRH. Although AVP is also produced by magnocellular neurons of the PVN and secreted from terminals in the posterior pituitary gland, various arguments support the view that AVP secreted from parvocellular CRH neurons represents the major potentiator of CRH mediated ACTH secretion (Whitnall, 1993; Kovacs & Sawchenko 1996). In rodents and humans, hypothalamic CRH neurons can occur in two pheno-types (Whitnall, 1993; Raadsheer, Sluiter, Ravid, Tilders, & Swaab, 1993; Raadsheer, Tilders, & Swaab, 1994b). Under resting conditions, only part of these CRH neurons belong to the AVP co-producing phenotype, i.e., co-express AVP mRNA, co-produce, co-store, and co-secrete AVP with CRH (De Goeij et al., 1992a; De Goeij, Dijkstra, & Tilders, 1992b; Whitnall, 1993; Bartanusz, Jezova, Bertini, Tilders, Aubry, & Kiss, 1993).

In collaboration with Verwer in Amsterdam, we found that the numbers of presumed CRH neurons that express AVP mRNA had increased 1-2 weeks after 1L-1 priming. This is in accordance with an increase in the fraction of CRH terminals that co-store AVP (Schmidt et aL, 1995a) and shows that IL-1 induces long lasting changes in the phenotypic expression of CRH neurons. Moreover, following a single IL-1 challenge, terminals of CRH neurons in the median eminence showed a delayed (>4 days) but long lasting (1-3 weeks) increase in AVP stores as illustrated in Fig 2. Therefore, the composition of ACTH secretagogues that are produced by hypothalamic CRH neurons is altered for prolonged periods of time after a single IL-1 exposure (Tilders & Schmidt, 1998). Peptide turnover studies (Schmidt et al., 1995a) further support the view that the signal which is produced by hypothalamic CRH neurons, had shifted towards AVP domination which is reminiscent of changes found after adrenalectomy, chronic stress (Whitnall, 1993; Tilders, Schmidt, & De Goeij, 1993; Aguilera, 1994), and depression (see below).

At the level of the pituitary gland, IL-1 priming did not affect steady state levels of POMC mRNA, POMC hnRNA, CRH receptor mRNA, and of CRH and vasopressin rcceptors (Tilders et al., in prep). However, alterations were disclosed when IL-1 primed animals were challenged to mount an ACTH response. In vivo studies revealed that IL-1 priming increased the ACTH response to an AVP challenge but attenuated the ACTH response to CRH. Thus, although the levels of CRH receptors and CRH receptor mRNA and their kinetics in the pituitary gland seem relatively intact, CRH effects in the pituitary gland are suppressed, which may hint to alterations in post-receptor mechanisms. Re-exposure of IL-1 primed rats to IL-1 revealed that the rapid down regulation of AVP receptors as seen in vehicle-primed animals was obliterated (Tilders et al., in prep). Thus, the mechanisms that appear to terminate AVP signaling in the pituitary gland are shut down in IL-1 primed animals, and AVP signaling is enhanced. The alterations in the pituitary gland therefore do not seem to compensate for the increased AVP drive by hypothalamic CRH neurons, but rather amplify the impact of enhanced AVP exposure during the challenge (see Fig 3).

In vivo studies further demonstrate that resting and stressor induced plasma

Figure 2. Long-lasting immune stimulus induced effects on hypo thalamic CRH neurons. Adult rats were given a single dose of human recombinant iriterleukiil-1 (IL-1) or vehicle (control). At various time intervals thereafter (1 —40 days) hypothalami of IL-1 primed and vehicle primed rats (n = 8) were processed for quantitative immunocytoehemical determination of CRH and vasopressin (AVP) in the external zone of the median eminence (terminals of hypophysiotropic CRH neurons). Note the delayed (>4 days) and long lasting (7-20 days) increase in AVP signal. *p < 0.05: S*p < 0.01 vs vehicle primed time-matched controls. For details see: Schmidt et al., 1995a.

Figure 2. Long-lasting immune stimulus induced effects on hypo thalamic CRH neurons. Adult rats were given a single dose of human recombinant iriterleukiil-1 (IL-1) or vehicle (control). At various time intervals thereafter (1 —40 days) hypothalami of IL-1 primed and vehicle primed rats (n = 8) were processed for quantitative immunocytoehemical determination of CRH and vasopressin (AVP) in the external zone of the median eminence (terminals of hypophysiotropic CRH neurons). Note the delayed (>4 days) and long lasting (7-20 days) increase in AVP signal. *p < 0.05: S*p < 0.01 vs vehicle primed time-matched controls. For details see: Schmidt et al., 1995a.

Figure 3. Schematic re pre sen tali on of immune-activation induced long-lasting alterations in hypothalamic CRH neurons and pituitary corticotropins. PVN: paraventricular nucleus of the hypothalamus where ccll bodies of hypophysiotropic ('R1 i neurons arc located. ZliME: external zone of the median eminence where the terminals of Ihcse neurons are located. Receptor mechanisms for CRH and AVP signaling are depicted as Vlb and CRH-1 respectively. For details see text.

Figure 3. Schematic re pre sen tali on of immune-activation induced long-lasting alterations in hypothalamic CRH neurons and pituitary corticotropins. PVN: paraventricular nucleus of the hypothalamus where ccll bodies of hypophysiotropic ('R1 i neurons arc located. ZliME: external zone of the median eminence where the terminals of Ihcse neurons are located. Receptor mechanisms for CRH and AVP signaling are depicted as Vlb and CRH-1 respectively. For details see text.

corticosterone levels of IT -1 primed rats were less sensitive to the suppressive actions of dexamethasone as compared to those in non-primed animals (Tilders et al„ in prep), which reflects a partial glucocorticoid feedback deficiency lor prolonged periods of time. The underlying processes may relate to alterations in glucocorticoid reccptor mechanisms in the pituitary gland and/or the brain. Alternatively, because AVP-mediated ACTH sccretion as compared to CRM-media ted ACTH secretion is rather insensitive to glucocorticoid inhibition (Abou-Samra, Catt, & Aguilera, 1986; Aguilera, 1994), this may as well be a reflection of the increased contribution of AVP to the control of ACTH secretion.

Although alterations at other levels cannot be excluded, the present findings strongly support the concept that long lasting alterations in hypothalamic CRH neurons and in pituitary corticotropin are instrumental in II. 1 induced long-lasting sensitization of the HPA system.

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