Military Strategies for Sustainment of Nutrition and Immune Function in the Field (1999) / Chapter Skim
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19 Inflammatory Stress and the Immune System
19 Inflammatory Stress and the Immune System
Pages 409-436
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From page 409... ...
Cytokines are glycoproteins/proteins produced by many cell types, including macrophages and monocytes, B- and T-lymphocytes, endothelial cells, fibroblasts, neurons, glia (microglia and astrocytes) , and some epithelial cells.
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From page 410... ...
in the rat. AP, area postrema; AVP, arginine vasopressin; CRM, corticotropin-releasing hormone; E, epinephrine; ME, median eminence; NE, norepinephrine; NTS, nucleus tractus solitarius; OVLT, organum vasculosum of lamina terminalis; PG, prostaglandin; PVN, paraventricular nuceus.
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From page 411... ...
Although responses to specific inflammatory, immune, or infectious insults are not necessarily identical, they provoke a similar central neuroendocrine response via the generation of similar cytokines and thus can all be viewed as "inflammatory stress." For purposes of discussion, these environmental perturbations can be viewed similarly not only because they induce a similar counterregulatory response (i.e., HPAA activation) but also because the consequences of this response expose the organism to similar immunosuppressive and anti-inflammatory actions following the initial induction of immune potentiating and inflammatory effects (Besedovsky and del Ray, 1996~.
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From page 412... ...
The major mechanism (Figure 19-1) mediating acute stimulation of ACTH secretion by IL-1 appears to involve CRH release (Baseman et al., 1989; Chrousos, 1995; Matta et al., 1990; Rivier, 1995; Sapolsky et al., 1987)
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From page 413... ...
Augmented CRH synthesis could maintain increased CRH release and therefore facilitate prolonged HPAA activation. In addition, centrally administered IL-1 increased AVP mRNA in PVN (Lee and Rivier, 1994)
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From page 414... ...
Stimulation of presumably transcription of an immediate early gene such as c-fos in the nucleus tractus solitaries of the medulla, which sends noradrenergic projections to the median eminence and PVN, could reflect neuronal activation by IL-1 and would support peripheral IL-1 stimulation of the brain via the nearby area postrema. In consonance with this view, neuroanatomical cuts caudal to hypothalamus inhibit HPAA activation by intravenous (iv)
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From page 415... ...
Despite beliefs that LPS stimulates the HPAA via induction of cytokines that acutely act pr~marily centrally, it seems likely that LPS may also stimulate ACTH and glucocorticoid secretion by generating cytokines that act directly on the anterior pituitary and possibly on the adrenal cortex. A variety of studies show that rats with hypothalamic resection, lesions, deafferentation, and pituitary stalk section (Elenkov et al., 1992; Makara et al., 1970, 1971)
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From page 416... ...
has found that peripherally (ip) administered LPS potently stimulates expression of IL-10 mRNA in specific brain regions including circumventricular organs (OVLT, median eminence, subLornical organ, area postrema)
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From page 417... ...
Arthritis Rat ADX Harbuzetal., (adjuvant) 1993 NOTE: Rx, treatment; IL, interleukin; TNF, tumor necrosis factor; ADX, adrenalectomy; HYPOX, hypohysectomy; DEX, dexamethasone; CORT, corticosterone *
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From page 418... ...
and exhibited at least a 200-fold increased sensitivity. Glucocorticoid Treatment in Adrenalectomized Animals This laboratory also wanted to determine whether glucocorticoid treatment in physiological quantities reflecting stress-stimulated CS secretion could protect rats against cytokines, as does an intact HPAA.
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From page 419... ...
These unique observations clearly demonstrated that complete protection against lethality induced by IL-1,B was afforded by glucocorticoid treatment In quantities approximating stress physiological CS secretion. Not only did these results show the lethal capability of a cytokine such as IL-10 in the face of a compromised HPAA, they also supported the hypothesis that physiological activation of the HPAA by immuneinflammatory response stimuli is a general means across species for counterregulating cytokine actions, modulating host defense immune~nflammatory reactions and ultimately protecting against potentially lethal actions of cytok~nes.
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From page 420... ...
had shown that IL-1 could directly stimulate CORT secretion from the adrenal after prolonged exposure, lethal responses to IL-ID in HYPOX rats suggested that direct stimulation of CORT secretion from the adrenal cortex by IL-1 ~ was not sufficient in vivo to protect against lethal actions by IL-I D, and supported the idea that cytokine actions directly at the level of the adrenal were not physiologically important. Earlier in this chapter, it was outlined that many studies (Baseman et al., 1989; Besedovsky and del Ray, 1996; Chrousos, 1995; Gaillard, 1994; Harbuz and Lightman, 1992; Rivier, 1995; Tilders et al., 1994)
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From page 421... ...
Considering the vital importance of glucocorticoid secretion and the protection derived from such secretion, it seems theologically reasonable that the stress axis might operate in a fail-safe, redundant manner with multiple back-up mechanisms for ultimately stimulating glucocorticoid secretion. INFLAMMATORY, IMMUNE, AND INFECTIOUS STRESS INDUCES PERIPHERAL IMMUNOSUPPRESSION AND ANTI-INFLAMMATORY EFFECTS Immune-neuroendocrine interactions and putative mechanisms mediating a protective neuroendocrine response against inflammatory, immune, or infectious stress have been described.
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From page 422... ...
endothelial cells, which produce cytokines, eicosanoids, and nitric oxide, a key molecule that mediates several features of LPS-induced septic shock. Glucocorticoids inhibit the transcription of IL-1,B mRNA, decrease mRNA stability, and diminish the efficiency of cytokine mRNA translation (Dinarello, 1992; Knudsen et al., 1987; Lee et al., 1988; Marx, 1995; Munck et al., 1984~.
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From page 423... ...
Protective Role of Sympathoadrenal Responses Stress activation of hypothalamic CRH neurons can also produce peripheral immunosuppression independent of glucocorticoids via stimulation of the sympathoadrenomedullary system (Friedman and Irwin, 1995) (Figure 19-2~.
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From page 424... ...
and the sympathetic nervous system.
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From page 425... ...
Neither is the general concept appreciated that central effects mediating alterations in brain function can produce peripheral immunosuppression and anti-inflammatory actions. AUTHOR'S CONCLUSIONS AND RECOMMENDATIONS During recent years, an increasing number of immune-neuroendocrine interactions have been identified and characterized that illustrate important bidirectional communication between these systems (Besedovsky and del Ray, 1996~.
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From page 426... ...
· Investigate in humans whether pretreatment with a specific regimen (based on specific doses and times) with a cytokine, LPS, or immunotherapy can temporarily modulate the immune system in a beneficially, protective manner against detrimental effects of inflammatory stress induced by inflammatory, immune, or infectious insults.
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1988. Adrenalectomy sensitizes mice to the lethal effects of interleukin-1 end tumor necrosis factor.
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1992. The role of interleukin-1 and tumor necrosis factor-a in the neurochemical and neuroendocrine responses to endotoxin.
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1988. Human recombinant interleukin-lp and -a, but not recombinant tumor necrosis factor-a, stimulate ACTH release from rat anterior pituitary cells in vitro in a prostaglandin E2 and cAMP independent manner.
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1993. Synergistic roles of interleukin-6, interleukin-1, and tumor necrosis factor in adrenocorticotropin response to bacterial lipopolysaccharide in vivo.
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1991. Tumor necrosis factor and interleukin-1 protection against lethal effects of tumor necrosis factor.
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1987. Tumor necrosis factor and interleukin-1 as mediators of endotoxin-induced beneficial effects.
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From page 433... ...
1989. Differential regulation of lipopolysacchar~de-induced interleukin-1 ar~d tumor necrosis factor synthesis: Effects of endogenous and exogenous glucocorticoids ar~d the role of the pituitary-adrenal axis.
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From page 434... ...
Those animals still had their stress response, still responded the same way, and it appeared to us that the redundancy of the system somehow had now turned on other mediators to do this. It particularly has to do with some of the brain work that you have done to show that the sympathetic nervous system is now being turned on and other hormonal regulation is coming to the fore.
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From page 435... ...
Because I think that will help elucidate some of these mechanisms. LEONARD KAPCALA: At the end of some of these studies where you give these small cytokine challenges or endotoxin, and you boost the immune response to a lethal subsequent dose, it would be interesting to study them [small cytokine changes]
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From page 436... ...
LEONARD KAPCALA: When our studies were performed, basically, what we were trying to do was to mimic what a maximal stress was, just showing that because, as you saw, the HPA axis of intact animals was completely protected so that these animals could tolerate very large doses. I would just like to make one other comment.
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