2001 Curt P. Richter awardHow circulating cytokines trigger the neural circuits that control the hypothalamic–pituitary–adrenal axis
Introduction
The rapid production of cytokines, chemokines and prostaglandins is an essential feature of the innate immune response. These proteins belong to the superfamily of pro-inflammatory molecules that are largely responsible for most of the autonomic/neuroendocrine changes that occur during the acute-phase response of all types of aggression. Tumour necrosis factor alpha (TNF-α), interleukin-1 (IL-1α and ß), IL-6, IL-10, IL-12, IL-15, IL-18 and type I interferons (IFN-α and IFN-ß) are cytokines that belong to the innate immune system, although they are not all pro-inflammatory (IL-10 is anti-inflammatory) and only a few of them are generally recognized to be potent modulators of the neuroendocrine system. Among them, TNF-α, IL-1ß and IL-6 are rapidly induced in response to foreign material and they can circulate into the bloodstream to act on distant organs.
Section snippets
TNF-α
TNF-α is a pleiotropic cytokine originally recognized for its anti-tumour activity (Carswell et al., 1975), but now referred to as a pro-inflammatory factor that plays a central role in initiating the cascade of other cytokines all together involved in a timely controlled immune response to infection. This cytokine is produced by a variety of cell types including neutrophils, activated monocyte/macrophages (Miller et al., 1993), T and B lymphocytes (Goldfeld et al., 1991), NK cells, astrocytes (
Interleukin-1
This pro-inflammatory cytokine (especially the ß form) is probably the most important molecule capable of modulating cerebral functions during systemic and localized inflammatory insults. There are two forms of IL-1, IL-1α and IL-1ß, that share less than 30% homology and bind to the same receptors. This explains the original thought that both molecules had similar biological activities, although the alpha form is no longer believed to be a potent player in the neural-immune interaction.
Interleukin-6 and gp130-related cytokines
Interleukin-6 (IL-6) is one of the most pleiotropic cytokines known that is involved in regulating a wide variety of immune functions, such as B- and cytotoxic T-cell differentiation, induction of IL-2 production and IL-2 receptor expression in T cells, T cell growth as well as the acute-phase reactions and hematopoiesis (Taga and Kishimoto, 1997, Hirano, 1998). A critical role of the pro-inflammatory cytokine in the acute-phase response was indeed reported in IL-6-deficient mice that exhibit a
How these circulating molecules talk with the brain parenchyma
The previous sections described three key players that are involved in the neural-immune interface and while both the systemic and cerebral cells can produce immune molecules, their contributions and mechanisms of action in modulating the neuroendocrine system are quite distinct. It is indeed very difficult to compare studies in which cytokines were injected systemically or centrally, because the receptors involved and the pathways are obviously very different despite a general outcome that may
PG synthesis by the cerebral microvasculature
The formation of PGs is initiated by the action of cyclooxygenase (COX, also known as prostaglandin endoperoxide H-synthase or PGHS), which catalyses two separate reactions; the first being the oxygenation of arachidonic acid to the unstable PGG2 by a cyclooxygenase function and the second, the subsequent reduction of PGG2 leading to a more stable PGH2 by peroxidase reaction. Although constitutive expression of the isoform COX-1 was found in various cell types, mRNA and protein levels remain
NF-κB and COX-2 in the cerebral endothelium
A robust activation of NF-κB is also detected in the endothelium of the brain capillaries in response to different systemic inflammatory stimuli (Laflamme et al., 1999, Laflamme and Rivest, 1999). Systemic LPS, IL-1ß and TNF-α injections provoke a rapid de novo expression of IκBα mRNA (index of NF-κB activity) in the endothelium of the brain blood vessels and parenchymal microglia (Laflamme et al., 1999, Laflamme and Rivest, 1999). The effects of IV IL-1ß and TNF-α take place rapidly (within
PGE2 is the key endogenous ligand within the CNS
We propose here that the microvasculature is the source of PG formation into the brain during systemic inflammatory challenges (LPS, IL-1 and TNF, but not IL-6) that trigger the NF-κB signalling pathways and COX-2 transcription within the cerebral endothelium. It is interesting to note that inflammation-induced NF-κB activity and COX-2 transcription is rather unspecific across the cerebral blood vessels and small capillaries, while the neuronal activity is limited to selective nuclei. PG
PGE2 receptors
Classic PG receptors comprise a family of eight genes encoding transmembrane G-protein-coupled receptors. These receptors are classified on the basis of selective affinities for naturally occurring prostanoids. There are distinct receptors for thromboxane A2, prostacyclins (PGI2), PGF2α, PGD2 and four different receptors for PGE2; EP1, EP2, EP3 and EP4 (Coleman et al., 1994, Narumiya et al., 1999). Multiple alternatively spliced isoforms exist for one of the PGE receptors (EP3) (Namba et al.,
The IL-6 story
Although IL-6 can stimulate the HPA axis directly at the level of both pituitary and adrenal glands, the cytokine is believed to trigger infundibular CRF secretion originating from parvocellular PVN neurons. It is therefore surprising that a single injection of IL-6 is insufficient to induce hypothalamic transcription of c-fos and CRF (Vallières et al., 1997), a phenomenon contrasting with the profound stimulation of these genes in the PVN of IL-1ß and LPS-injected rats (Rivest and Rivier, 1994
IL-6 signalling cascade in the CNS
The bacterial endotoxin triggers transcription of the gene encoding the suppressor of cytokine signalling 3 (SOCS-3) in all the CVOs and their adjacent structures, chp, the ependymal lining cells of the cerebroventricular system and along the endothelium of the cerebral capillaries (Lebel et al., 2000). This indicates that IL-6 can trigger the JAK/STAT signalling in these groups of cells that may allow the transcription of the target genes involved in the neural-immune interface. A single
Proposed cascade of events and concluding remarks
- 1.
Circulating molecules produced by systemic inflamed sites target cells of the BBB to release intermediates in the brain parenchyma.
- 2.
IL-1ß is the most likely candidate to mediate the early effects during systemic and localized insults, but not during endotoxemia (Laflamme et al., 1999).
- 3.
The binding of IL-1ß to its type I receptor and IL-1R-AcP engages the IRAK/TRAF6/MyD88/NIK/IKK pathway responsible to trigger COX-2 gene transcription in the cerebral endothelium.
- 4.
Activation of the COX-2 enzyme
Acknowledgments
This work is supported by the Canadian Institutes of Health Research (CIHR; the former Medical Research Council of Canada (MRCC)). The author is a MRCC Scientist and holds a Canadian Research Chair in Neuroimmunology.
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