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(Journal of Leukocyte Biology. 2003;73:417-427.)
© 2003 by Society for Leukocyte Biology

Endogenous versus exogenous glucocorticoid responses to experimental bacterial sepsis

Richard Silverstein* and Donald C. Johnson{dagger}

Departments of
* Biochemistry and Molecular Biology and
{dagger} Molecular and Integrative Physiology, University of Kansas School of Medicine, Kansas City

Correspondence: Richard Silverstein, Ph.D., University of Kansas Medical Center, Department of Biochemistry and Molecular Biology, 3901 Rainbow Blvd., Kansas City, KS 66160-7421. E-mail: rsilvers{at}kumc.edu


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ABSTRACT
 
Although lack of adrenals dramatically reduces resistance against sepsis generally, the value of glucocorticoid levels above those normally produced by stress remains controversial. An early and long-held concept is that glucocorticoid protection against lipopolysaccharides in animal models is important. Supporting this concept, C3H/HeJ mice, lacking Toll-like receptor-4 (TLR-4), and consequently, endotoxin hyporesponsive, have recently been shown to be resistant to glucocorticoid protection against live Escherichia coli. Effective antibiotic intervention, as an additional parameter and with concomitant administration of glucocorticoid, not only allows for expected antibiotic protection but also for glucocorticoid protection against E. coli or Staphylococcus aureus of mice sensitized to tumor necrosis factor {alpha}, regardless of the status of the TLR-4 receptor. TLRs, including but not limited to TLR-2, may be involved in glucocorticoid protective efficacy against Gram-positive and Gram-negative sepsis. Overlapping and possibly endotoxin-independent signaling may become important considerations.

Key Words: TNF • imipenem • Toll-like receptor • antibiotic • LPS • Gram-positive


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INTRODUCTION
 
The past 10–15 years have witnessed a gradual change in emphasis in the bacteria and bacterial component(s) that are most commonly being used in experimental animal models of sepsis. Although such models have long included challenge with live Gram-negative and Gram-positive bacteria [1 , 2 ], most of the earlier studies, as previously reviewed [3 ], used purified lipopolysaccharide (LPS) as the challenging agent. Some of those studies included demonstrations of the protective efficacy against lethality provided by endogenous and/or exogenous glucocorticoids, with the associated down-regulation of tumor necrosis factor {alpha} (TNF-{alpha}) expression. Specific related developments are summarized in Table 1 .


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  		Table 1. Chronological Summary of Early Studies into the Mechanism, Scope, and Limitations of Glucocorticoid Protection against LPS and TNF-{alpha} Lethality in Animal Models

For glucocorticoids to increase resistance to pathogens, even in animal models, one of the disturbing concerns continues to be the need for pretreatment, or at least concomitant treatment, with respect to the time of challenge [14 ]. This, in turn, has served to increase interest in identifying and assessing what it is that is most crucial in the innate-immune response, which leads to antagonistic action against glucocorticoids. Such interest has continued from Berry’s glucocorticoid antagonizing factor, as reviewed in ref. [3 ], to more recently, the proposed glucocorticoid counter-regulator macrophage migration inhibitory factor, reportedly acting through Toll-like receptor 4 (TLR-4) [14 15 16 17 ].

Timing of glucocorticoid administration is also important in relation to antibiotic chemotherapy. Johnston and Greisman [18 ] observed that methylprednisone protected mice against the lethal effects of Proteus mirabilis only when it was given in conjunction with antibiotic therapy and then only when given at the same time as the first dose of antibiotic. Moreover, these authors were able to link protection provided by the glucocorticoid to its action against the effects of endotoxin. We have reported, in collaboration with Morrison [19 , 20 ], another example of concomitant antibiotic treatment potentiating glucocorticoid protection but in this instance, against the lethal effects of a Gram-positive organism, Staphylococcus aureus M. Specifically, DEX was found ineffective at protecting mice against live S. aureus, except when it was administered concurrently with effective antibiotic (imipenem or ceftazidime) therapy. As we shall consider later, such glucocorticoid protection appears to occur via an endotoxin-independent mechanism. An endotoxin-independent mechanism can even be seen against Escherichia coli, provided that the mice are endotoxin hyporesponsive (C3H/HeJ) and again, with the glucocorticoid given at the same time as the antibiotic.

The concept that chemotherapeutic bacterial killing can, of itself, lead to a detrimental host inflammatory response has come to be known as the Jarisch-Herxheimer reaction, derived from early studies by these workers against syphilis [21 , 22 ]. The Jarisch-Herxheimer reaction has long come to be appreciated as a potentially serious detriment to maximal efficacy of antibiotic therapy [23 ], including a potential danger from subsequent, uncontrolled TNF-{alpha} release [20 , 24 , 25 ]. The impact of such phenomena on the timing, mechanisms, and ultimate efficacy of glucocorticoid protection is a pertinent consideration. Unfortunately and despite the prescient study by Johnston and Greisman [18 ] noted above, the potential application of inter-related glucocorticoid-antibiotic treatment has yet to be systematically investigated in relationship to the innate-immune response. Thus, in this particular review, inter-relationships between antibiotic and glucocorticoid treatments will be emphasized. One aspect of the glucocorticoid defense against sepsis that does not involve therapeutic timing considerations is that associated with endogenous glucocorticoids, and it is to this phenomenon we now turn.


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ENDOGENOUS GLUCOCORTICOID PARTICIPATION IN HOST DEFENSE AGAINST SEPSIS
 
There is convincing evidence from studies with mice that had been adrenalectomized (ADX), hypophysectomized, or glucocorticoid receptor-inactivated by Mifepristone (RU 486) that the glucocorticoids synthesized via the hypothalamic-hypophyseal-adrenal axis are critically important to host defense against endotoxin [3 , 9 10 11 , 14 ]. In addition, following challenge with LPS, there was a particularly marked increase in serum TNF-{alpha} in ADX mice [26 , 27 ], which was significantly larger than that found in hypophysectomized mice [26 ]. Similar experiments conducted in our laboratory but with challenge from live E. coli have confirmed qualitatively similar results as those seen previously by us [26 ] and by others [27 ] with LPS (Fig. 1A ). The ADX mice exhibited a 100-fold greater lethal sensitivity to the E. coli than sham-operated controls, and the LD50 decreased from 7 x 106 to 6 x 104 cfu per mouse. Administration of 4 mg/kg DEX at the time of challenge provided intact and ADX mice increased resistance against the lethal effects of E. coli. The LD50 of both groups was increased to a common level, 2–3 x 107 cfu per mouse. These experiments, in the absence of antibiotic treatment, correspond to a threefold increase in the LD50 for intact mice and a 500-fold increase for ADX mice.



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  		Figure 1. Comparison of the TNF response to challenge from E. coli O111:B4 (A) versus S. aureus M (B) of ADX versus intact CF-1 mice. Conditions are comparable with those of lethality studies (Table 2) . The time of the response to E. coli [20 ] parallels that from LPS, e.g. [26 , 27 ], while appearing several hours earlier than the TNF response to S. aureus. It should be emphasized that these data and those presented in Table 2 were obtained in the absence of antibiotic treatment. TNF-{alpha} was determined by cytotoxicity assay [20 ], data ± SEM, five mice per datum; *, P < 0.05. Controls had been sham-operated at the time of adrenalectomy. Surgery and recovery were as described previously [26 ]. Mice were 8–10 weeks, females. E. coli, 108 colony-forming units (cfu) per mouse.

Lethality from live S. aureus under otherwise identical conditions to those with E. coli and again in the absence of antibiotic treatment revealed a much different picture, as summarized in Table 2 . Adrenalectomy sensitized the mice to S. aureus by only fivefold, decreasing the LD50 from 5 x 105 to 1 x 105 cfu per mouse, in contrast with the 100-fold decrease in the LD50 in response to E. coli as just noted. Correspondingly, DEX treatment (4 mg/kg at the time of challenge) of ADX mice was able to confer only a fivefold increase in resistance against S. aureus, as compared with a 500-fold increase against E. coli. Finally, in mice with intact adrenals, as we previously reported [19 ], DEX not only did not protect against lethality from S. aureus but resulted in a twofold increased lethal sensitivity.


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  		Table 2. Lethal Challenge from S. aureus in Contrast to that from E. coli Is Relatively Insensitive to Glucocorticoid Deprivation or Glucocorticoid Supplementation

Glucocorticoid protection against LPS and against Gram-negative bacteria is, at least in part, TNF-targeted, as has been well documented and as previously reviewed [3 , 14 ] (see also Table 1 ). Accordingly, and in light of the data of Table 2 discussed above, it becomes increasingly important to determine the TNF response to S. aureus and the ability of glucocorticoid to attenuate that response. As shown in Figure 1B , the TNF-{alpha} response to S. aureus came later than that from E. coli. It is, however, still rising by 5.5 h. Later time measurements were not taken as a result of the moribund state of the animals. Among ADX mice, the magnitude of the TNF peak in response to E. coli was fivefold greater than that from S. aureus even at 5.5 h. To assess whether the inability of DEX to protect against S. aureus lethality might conceivably result from failure of DEX to attenuate the TNF response, 4 mg/kg DEX was given at the time of S. aureus challenge of intact and ADX mice. Under such conditions, the TNF response was nevertheless reduced at 5 h from 8.5 to 0.8 ng/ml for intact mice and from 24 to 1.3 ng/ml for ADX mice. Corresponding reductions were also seen at 5.5 h, from 20 to 0.8 ng/ml and from 59 to 1.2 ng/ml, respectively (data not shown).

Thus, in the absence of antibiotic treatment, endogenous and exogenous glucocorticoid exhibited a measure of protection against E. coli. Conversely, exogenous or endogenous glucocorticoid had, again in the absence of antibiotic treatment, little substantive effect against S. aureus lethality.


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CLINICAL PERSPECTIVES
 
It has long been recognized that the effects of glucococorticoids can be a double-edge sword, and high doses represent a serious, potentially long-term, as well as short-term, danger as a result of their toxicity [28 ]. As there can be little doubt that glucocorticoids can, under some circumstances, reduce serum TNF-{alpha} levels, even from an anti-TNF perspective, under some circumstances, glucocorticoids may conceivably prove detrimental. Thus, in one anti-TNF-targeted clinical trial, treatment of septic shock with a soluble type II TNF receptor:Fc fusion protein led to a significantly increased number of deaths, dose-dependent, in the subgroup of patients with Gram-positive organisms [29 ].

In this review, it is not the intent to present a comprehensive assessment of the use of glucocorticoids against human sepsis, a subject of ongoing, active interest [30 31 32 33 34 35 36 37 38 39 ]. Nevertheless, certain features of that development should be noted. Studies of adrenal insufficiency in the cecal ligation and puncture model have indicated that adrenal insufficiency may prove to be particularly important in late sepsis [32 ]. Annane et al. [30 ] have recently reported in a 7-day treatment trial that low doses of hydrocortisone and fludrocortisone improved survival from septic shock and relative adrenal insufficiency without increasing adverse effects throughout the 28-day monitoring period. Further, Annane [39 ] has cautioned that high doses of corticosteroids should not be given in severe sepsis, except under very specific circumstances, such as bacterial meningitis in children. In another study, Bollaert et al. [34 ] were able to show that administration of 100 mg cortisone intravenously for 5 days had a significant improvement in hemodynamics and a beneficial effect on survival from late septic shock.

These developments and the prescient study of Johnston and Greisman noted above [18 ] suggest that systematic examination of inter-related glucocorticoid-antibiotic treatments may yield still further improvement, depending in part on the knowledge that may be brought to bear as to the particular microbes involved.


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CAN ANTIBIOTIC AND EXOGENOUS GLUCOCORTICOID PROTECT IN CONCERT?
 
Antibiotic killing of S. aureus in mice had a marked influence on the innate-immune response in a number of distinct respects. Examination of the increased serum TNF-{alpha} levels following S. aureus challenge revealed a more rapid response than in the absence of antibiotic [20 ]. This shift in kinetics paralleled differences in TNF-{alpha} release seen upon stimulation of peritoneal macrophages in vitro [40 ]. However, inducible nitric oxide synthase (iNOS) levels were altered in the opposite direction, being correspondingly reduced [41 ]. These changes were evident at the mRNA and protein levels. These differences were qualitatively and quantitatively distinct from those seen with E. coli. In vivo killing of E. coli by antibiotics was found to have no apparent effect on the magnitude or the kinetics of serum TNF-{alpha} appearance [20 ]. Again, comparable results were observed in vitro [40 , 41 ]. In addition, iNOS levels were found to increase in response to E. coli in contrast to the decrease seen with S. aureus [41 ].

One could speculate that such marked differences in host response might reflect differences in bacterial components that are released in response to antibiotic treatment. These, in turn, might account for differences in the ability of glucocorticoid to provide protection beyond the differences already noted above in the absence of antibiotic treatment.

Figure 2 summarizes published [19 , 20 ] and unpublished results from our laboratory relating to the capacity of glucocorticoid (DEX, 4 mg per kg, intraperitoneally) to protect mice against lethal sepsis when given at the time of bacterial challenge from E. coli or S. aureus. Results obtained with effective antibiotic (imipenem) chemotherapy (right panels, B and D) or without antibiotic treatment (left panels, A and C) are to be compared. The D-galactosamine model was used to sensitize the animals to the lethal effects of TNF-{alpha} [42 ]. To separate the effects of endotoxin from those of other bacterial components that might be implicated, results with normal mice (CF-1; Fig. 2 , upper panels, A and B) are to be compared with those from mice that are endotoxin hyporesponsive (C3H/HeJ; Fig. 2 , lower panels, C and D).



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  		Figure 2. DEX protection against S. aureus M and E. coli O111:B4 lethality following concomitant administration with imipenem (right panels, B and D) versus saline vehicle (left panels, A and C) to D-galactosamine-treated CF-1 mice (A and B) or D-galactosamine-treated C3H/HeJ mice (C and D) [19 , 20 ]. S. aureus M challenge of C3H/HeJ mice (lower panels, C and D) versus CF-1 mice (upper panels, A and B). Imipenem, 20 mg/kg, and DEX, 4 mg/kg, were each given by separate injection at the time of challenge.

From all of the data in the right panels of Figure 2 , it is evident that DEX conferred appreciable protection beyond that from antibiotic chemotherapy, regardless of whether challenge was from E. coli or S. aureus. In contrast, DEX was ineffective against S. aureus in the absence of antibiotic chemotherapy for CF-1 mice and C3/HeJ mice (Fig. 2 , left panels).

With E. coli, the ability of DEX to protect normal mice was confirmed in this model and as expected, was most likely directed against LPS. Thus, protection was not seen in the C3H/HeJ mice (Fig. 2C) . With antibiotic chemotherapy at the time of challenge, DEX protection is seen to "reappear" in these endotoxin-hyporesponsive mice (Fig. 2D) , suggesting that the effect of the DEX was distal to the effect of LPS interacting with its receptor, i.e., TLR-4.

In summary, the ability of DEX to confer protection can be linked to antibiotic treatment, and with Gram-positive and Gram-negative bacteria, such (additional) protection can be TLR4-independent. The effect of which bacterial component(s) of Gram-negative bacteria within such a framework may prove to have been targeted by the action of DEX is unclear. It is nevertheless noteworthy that a peptidoglycan-associated lipoprotein (PAL) released from E. coli during Gram-negative sepsis becomes lethal to D-galactosamine-sensitized C3H/HeJ mice [43 ]. Previous studies have shown that a platelet-activating factor (PAF) from neutrophils plays a large role in the lethality associated with TNF-{alpha}/galactosamine [44 ]. Further, it has been suggested that the C3H/HeJ defect may lie within the PAF pathway [45 ]. The relationship between PAL and PAF is not clear. The substantial reduction in lethality associated with E. coli lacking PAL synthesis or producing a mutant PAL underscores the specificity of its response [43 ]. There are, of course, additional components that must be considered among Gram-negative and Gram-positive bacteria (discussed in ref. [43 ]), and a brief summary of our current knowledge of the effects of antibiotic killing on their release, their relationship to the innate-immune response, and glucocorticoid action against that response is to be considered next.


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BACTERIAL COMPONENTS
 
Gram-positive and Gram-negative bacterial components that elicit an innate-immune response include, in addition to peptidoglycan-associated lipoprotein discussed above [43 , 44 ], those found only in Gram-negative bacteria, only in Gram-positive bacteria, or both. Most attention has been directed toward LPS, a potent and potentially lethal component found exclusively in Gram-negative bacteria. Increasingly, however, attention is being directed toward the actions of lipoteichoic acid (LTA), found exclusively in Gram-positive bacteria, to peptidoglycan (PG) and most recently, bacterial CpG DNA of Gram-positive and Gram-negative organisms [46 47 48 49 50 51 ].

As discussed above and as previously reviewed [3 , 14 ], there is a considerable history reflecting the capacity of endogenous and exogenous glucocorticoid in animal models to protect against the lethal effects of LPS. Such protection is correspondingly conferred by these hormones against the lethal effects of live, Gram-negative bacteria. It is, however, essential to also consider the actions of glucocorticoids against other bacterial components, particularly given the increasing concern toward Gram-positive sepsis [46 , 49 , 52 53 54 55 ].

Pretreatment of rats with 3 mg per kg DEX, 2 h before challenge, has been shown to attenuate elements of the host response resulting from concerted challenge with LTA and PG [53 ]. These include, among others, a reduction in TNF-{alpha} and iNOS as well as a reduction in the serum levels of enzyme markers associated specifically with hepatocellular injury [53 ]. Studies from the same laboratory showed that specific moieties of LTA and PG were involved in these responses and that combinations of LTA with a foreign PG obtained from nonpathogenic strains of S. aureus did not have the same actions [54 , 55 ]. However, whether these conclusions extend to other species is questionable [56 ]. It is noteworthy that enhancement of the innate-immune response is not restricted to synergy between LTA and PG. Synergistic enhancement of the host immune response has also been reported for other bacterial components, including LPS + bacterial CpG DNA [50 , 51 ], LPS + PG [53 54 55 56 ], and muramyldipeptide + LPS or LTA [57 ]. The mechanistic basis for such synergy is unclear, but the fact that different classes of bacterial components bind to different TLRs suggests that distinct, yet interactive, signaling pathways may be involved [58 59 60 61 62 63 ].

The degree of severity associated with this synergistic behavior remains unclear, as does the effectiveness of glucocorticoids in addressing its consequences. Nevertheless, in the case of antibiotic treatment against infection with S. aureus, there is now experimental evidence in animal models for each step of a sequence that may be considered to proceed from antibiotic-linked release of LTA + PG to synergistic action of LTA + PG, leading ultimately to multiple organ failure with beneficial action resulting from DEX administration at the time that antibiotic treatment is initiated [20 , 53 , 56 , 64 65 66 ]. With respect to Gram-negative bacteria, there has, of course, long been an interest in the role of antibiotics in the rate of LPS release [67 68 69 ] and of bacterial components generally [70 ].


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TNF-{alpha} RELEASE LINKED TO ANTIBIOTIC CHEMOTHERAPY
 
In the absence of antibiotic, the increase in serum TNF-{alpha} associated with a lethal challenge from S. aureus appeared 3 h into the challenge and continued to rise (Figs. 1B and 3 ) [20 ]. By contrast, the serum TNF-{alpha} response elicited upon concomitant treatment with antibiotic (imipenem or ceftazidime) appeared much earlier and was essentially gone by 3 h. These effects were also observed and were accentuated in ADX mice (Fig. 3) . When lethality was ascertained with intact, TNF-{alpha}-sensitized (D-galactosamine-treated) mice, imipenem was found to protect 70-fold against the S. aureus. DEX not only did not protect but slightly increased lethality. The combination of imipenem and DEX, by contrast, conferred 10,000-fold protection. In parallel experiments with ADX mice, imipenem alone provided 3000-fold protection, and DEX alone protected fivefold. Imipenem + DEX protected 50,000-fold. These results coupled with those previously discussed in this review demonstrate that glucocorticoid had little effect on S. aureus lethality in the absence of antibiotic treatment. This, however, changed dramatically with inclusion of timely antibiotic treatment. As glucocorticoid protection was potentiated, there was, in addition, a change in the kinetics and magnitude of the TNF-{alpha} response, and a TNF-{alpha} peak appeared soon after the time of concurrent initiation of the antibiotic and glucocorticoid treatments.



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  		Figure 3. TNF response to imipenem-killed S. aureus M in ADX versus intact CF-1 mice. Imipenem dose, 20 mg/kg, given at the time of challenge. TNF-{alpha} was determined by cytotoxicity assay [20 ], data ± SEM, five mice per datum; *, P < 0.05. The antibiotic treatment reduces the magnitude of the overall TNF response (cf. with the profiles of Fig. 1B ) and shifts it to earlier times, as might be anticipated in a Jarisch-Herxheimer response. Surgery and recovery were as described previously [26 ]. Mice were 8- to 10-week-old females. S. aureus, 108 cfu per mouse.

Ex vivo [40 , 41 , 67 , 69 , 71 , 72 ] and in vivo [20 ] studies of cytokine and chemokine response to bacteria or their components, in concert with antibiotic intervention, are of increasing interest, and inevitably, this should result in improved therapeutic intervention strategies, including those derived in part from corresponding studies of glucocorticoid efficacy.


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GLUCOCORTICOID PROTECTION AGAINST PROLIFERATING BACTERIA
 
Twenty-one bacterial isolates (10 Gram-negative and 11 Gram-positive) were tested in mice in terms of susceptibility to D-galactosamine-sensitized lethality and corresponding protection by DEX (4 mg per kg intraperitoneally) given at the time of challenge. In parallel with our findings with E. coli O111:B4 [19 , 20 ] and S. aureus M [19 , 20 ], D-galactosamine was found to sensitize mice to all 10 Gram-negative bacterial isolates, and DEX conferred significant protection against all of them. These included four strains of Klebsiella pneumoniae, three strains of E. coli (including E. coli O111:B4), and one each of Citrobacter diversus, P. mirablis, and Pesudomonas aeruginosa. In contrast, D-galactosamine did not sensitize, and DEX did not protect mice challenged with any of the six S. aureus isolates, including S. aureus M. It is interesting that the results with Streptococcus mitis and Streptococcus pneumoniae paralleled those with S. aureus, but those with the three Enterococcus faecalis isolates did not [73 ].


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ARE WE ASKING THE WRONG QUESTION?
 
As discussed in this brief review, there is considerable evidence that endogenous and exogenous glucocorticoid, under some circumstances, can increase resistance not only to the action of bacterial components but more importantly to intact bacteria. Why, then, is there controversy over clinical efficacy (e.g., refs. [74 75 76 77 78 79 ])? In animal models, the question of timing of glucocorticoid administration relative to that of bacterial or bacterial component challenge, which cannot be realistically addressed clinically, has long been of concern. Another aspect of timing that appears to be important and which can be addressed is that of the timing of glucocorticoid treatment relative to that of front-line antibiotic therapy. If that is not properly considered, glucocorticoids may conceivably not only become ineffective but may prove potentially harmful.


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CORTICOSTEROIDS AND IMMUNITY
 
Of all the functions and physiological actions of the adrenal corticosteroids, and particularly those with clinical implications, none has received more attention than those related to the immune system. Review of this enormous literature has become nearly impossible and certainly well beyond the scope of the present discussion. The resistance to disease offered by the presence of the adrenal has been recognized for more than 100 years [78 , 79 ], although the involvement of the corticosteroids and their actions through nuclear transcription factors are relatively recent (reviewed in refs. [80 81 82 83 ]). Therefore, it seems somewhat surprising that there remains considerable confusion concerning which mechanism(s) of the glucocorticoids are important for the consequences of nonspecific as well as infection-induced stresses. Much of this confusion can be related to the great variety of studies that have been performed using many different kinds of cells, cell lines, animal models, or patients with a variety of pathological conditions. There is also the use of a variety of glucocorticoids, particularly potent synthetic steroids such as DEX, whose effects can be significantly different from those of endogenous glucocorticoids [84 ]. The results of these studies have been reviewed several times ([82 , 85 ] and references therein), but the validity of many of the specific interpretations that have been proposed has been questioned [86 ].

What is not in question, however, are the consequences of sepsis associated with a loss of adrenocortical function by adrenalectomy [9 , 27 , 78 , 79 , 82 , 86 , 87 ], by disease ([88 ] and references therein), or upon loss of hypothalamic-hypophyseal control of the adrenals [85 ]. The principal effect of adrenocortical insufficiency is loss of control over homeostatic mechanisms such that a large variety of nonspecific damaging agents, which include bacterial infections, produce a variously defined state referred to as shock; i.e., the body is unable to satisfactorily adapt to an altered, internal environment (refs. [78 , 85 ] for discussions). Selye [78 ] in outlining his General Adaptation Syndrome characterized shock as a combination of nervous depression, hypothermia, hypovolemia, tissue catabolism, as well as other signs of "damage". When induced by responses to infectious agents, shock can progress to increasingly more profound, physiologic dysfunctions, generally referred to as septic shock, which all too often results in death [88 , 89 ]. Although the ultimate cause of death in shock is usually referred to as "multiple organ failure", the mechanisms involved are variable and not easily defined [88 ]. The reason for the latter is related to the difficulty in determining cause and effect when dealing with the large number of complex, cooperating, cybernetic systems such as those involved in the maintenance of life-sustaining homeostasis. The complexity found in networking interactive signaling pathways activated by a variety of receptors has recently received attention [90 , 91 ]. Quite obviously loss of adrenocortical function and of glucocorticoids in particular is inconsistent with survival, as the body is left almost totally defenseless against all types of stresses [78 , 92 ].

Understanding a role for glucocorticoids in protecting against the lethality of septic shock is important for the present discussion. Selye [92 ] introduced the idea that some hormones, termed "syntoxic", function by adjusting the body’s response so that it tolerated but did not attack pathogens. Using this definition, some actions of adrenal corticosteroids would be considered to belong to this group. Other hormones, which he called "catatoxic", actually destroyed the aggressor, and some actions of corticosteroids would also fit this definition. The fact that some microorganisms or antigens are comfortably accommodated, and others result in a robust, multimechanism attack is consistent with Selye’s concept. Also important for this discussion is the recently proposed "danger model" of Matzinger [93 ], whereby the immune system only responds to what the body recognizes as producing dangerous consequences, regardless of whether they represent self or nonself. The mechanisms involved in sensing this danger are not clear, but we could imagine that "syntoxic" hormones, including glucocorticoids, could play a role by maintaining monitoring systems for many physiological processes, including the immune system. With lack of glucocorticoids, there would be loss of such monitors, and consequently, almost everything becomes dangerous including activation of the immune system.

Today, we would probably consider "catatoxic" hormones in terms of those that could increase expression of phase I drug-metabolizing enzymes, typically cytochromes P450 (CYPs) [94 , 95 ]. They also may be important for induction of the genes controlling the expression of phase II or conjugation enzymes, which act on the products of phase I enzymes [94 ]. The CYPs consist of a highly conserved family of several hundred isoforms that can react with a great many substrates [94 , 95 ]. They are usually associated with the liver, but they are present in nearly all tissues. A large number of microorganisms also express multiple forms of CYPs, but they are absent in E. coli [96 ]. Upon bacterial killing, these CYPs could obviously serve as foreign antigens for immune responses. The CYP oxygenases destroy the activity of many xenobiotics that could be detrimental to normal body functions, but some of their products can be even more dangerous than their substrates [94 , 95 ], and this could play a role in recognizing "danger".

Schuetz and Guzelian [97 ] reported that several glucocorticoids could regulate induction of CYPs and that DEX was the most effective, being ~70 times more potent than the endogenous hormones corticosterone or cortisol. It is important to realize, however, that a great many agents, including antibiotics, have the ability to induce the CYP enzymes. An example of the latter is Rifampin, an antibiotic used against S. aureus infections, which induces CYP oxidative enzymes that have significant interactions with a large number of compounds including glucocorticoids [98 ]. Furthermore, erythromycin belongs to the same class of CYP inducers as does DEX [96 ].

The results of many studies have contributed to our understanding of the molecular mechanisms involved in glucocorticoid action. These have been recently reviewed [80 81 82 83 ], although there is the caveat that not all mechanisms apply to all kinds of cells. Briefly, these steroids diffuse through the cell membrane and bind a cytosolic transcription factor (GR) that has two heat-shock proteins (HSP) attached. Ligand binding releases the HSP and allows transfer of GR to the nucleus where it can interact with specific promoter elements of specific genes. There is also evidence for protein–protein interactions between the GR and other transcription factors [80 81 82 83 84 85 ]. Of these, most attention has been given to nuclear factor (NF)-{kappa}B, and there are many investigators who would consider GR interaction with this transcription factor to be the primary function of glucocorticoids. What makes NF-{kappa}B particularly attractive as a general agent for glucocorticoid action is the lack of specificity for the stress factors involved.

Recent attention has focused on the interactions between two forms of GR, both products of the same gene [83 , 95 ]. GR{alpha} binds glucocorticoids and interacts with the glucocorticoid response elements of genes that produce increased or decreased expression of specific cellular proteins. Conversely, GRß, which is produced in greater abundance by cells in response to some proinflammatory cytokines and has a longer half-life than the {alpha} form, does not bind glucocorticoid ligands and can act as an inhibitor of GR{alpha} action [82 , 83 ]. Therefore, GRß could be considered proinflammatory in the sense that it is anti-antiinflammatory. However, there is some controversy over the importance of GRß in the effects of glucocorticoids, as this receptor is not found in all species [83 ].

Current attention is focused on the genes that are associated with glucocorticoid actions and their relationship to immune responses. Use of microarrays appears to hold promise with regard to which genes should be more carefully examined when considering initiation or inhibition of immune responses [99 100 101 ]. Wang et al. [99 ] reported that heat-killed S. aureus, purified peptidoglycan, or endotoxin increased expression of 120 of the array of 600 genes in human monocytes. Chemokines, particularly interleukin (IL)-8 and macrophage-inflammatory protein-1{alpha}, were among the principal genes up-regulated. It is important that a unique pattern of genes was associated with each bacterial component. A recent DNA microarray study [101 ] involving 9182 genes of activated or nonactivated peripheral blood mononuclear cells exposed to 10-7 M DEX for 18 h revealed that 9% of the genes under consideration appeared to be down-regulated, and 12% were up-regulated; i.e., 78% were unchanged. It is interesting that the ratio of up-regulated-to-down-regulated genes was greater for those associated with the innate-immune system than those of the adaptive-immune system. Future studies will require inclusion of proteomics so that the importance of translations of mRNA can be evaluated.

Important for our current consideration are the possible mechanisms responsible for the lack of glucocorticoid protection for intact or ADX mice challenged with live S. aureus, while providing such a profound increase in protection against the antibiotic-killed S. aureus. This is in contrast to the considerable and comparable protection provided by glucocorticoid against the lethal effects of live or antibiotic-killed E. coli. Explanations for these differences would certainly have to include consideration of cellular TLRs/IL-1-like receptors, which belong to the family of pattern recognition receptors (PRR) that interact with pathogen-associated molecular patterns (PAMPs) of Gram-positive or Gram-negative bacteria, as well as differences in their signal transduction systems [58 59 60 61 62 63 ]. The TLR/IL-1-like receptor family is made up of 10 membrane proteins ([102 ] and references therein), which in concert with adaptor proteins, bind PAMPs and activate signaling systems that stimulate production of proinflammatory cytokines. Mice deficient in TLR-4, by mutations (C3H/HeJ; C57BL/10ScCr) or induced by knockout technology, are hyporesponsive to Gram-negative bacteria and particularly LPS but not to Gram-positive bacteria [60 ]. Conversely, TLR-2 is generally considered one of the principal receptors for Gram-positive bacterial components [62 ]. With Gram-negative and Gram-positive bacteria, however, pattern recognition by more than a single TLR appears essential for maximal responses [58 59 60 , 102 , 103 ]. The same selectivity of receptor for response to bacterial components does not extend to other agents that stimulate the immune system. For example, HSP activate immune cells to produce cytokines by TLR-2 or TLR-4 [104 ]. Equally important for activating the signaling pathways associated with the various PRR are adaptor proteins, such as MyD88 or TLR/IL-1 receptor-associated protein [58 , 59 ]. The TLR signaling pathway involves activation of the mitogen-activated protein kinases (MAPKs), which ultimately activate NF-{kappa}B for production of cytokines [58 , 103 ]. Although TLR-2 also participates in the response to Gram-negative bacterial components, it does not do so via the same pathway used by TLR-4 [59 ]. Li and his associates [105 ] have recently reported that a component in Gram-negative, nontypeable Haemophilus influenzae is important for up-regulation of TLR-2 expression in HeLa and primary human airway epithelial cells. The expression was a product of a stimulatory signaling system that involved IKKß phosphorylation of I{kappa}B{alpha}, necessary nuclear transfer of NF-{kappa}B, as well as an inhibitory signaling system involving p38{alpha}/ß MAPK. Most importantly, they found that glucocorticoid enhanced the expression of TLR-2 by inhibiting the negative effect of p38 MAPK kinase by increasing expression of the phophatase mitogen-activated protein kinase phosphatase-1 (MKP)-1; whether the glucocorticoid had any other direct or indirect effects on TLR-2 expression is unresolved [106 ]. Kassel et al. [107 ] suggested that stabilization and increased expression of MKP-1 by the liganded glucocorticoid receptor may be a common action of glucocorticoids in many kinds of cells of the immune system. They demonstrated that MKP-1 inhibited extracellular regulated kinase (ERK)1/2 activity, but the mechanism(s) remain unclear. These results are consistent with the view expressed by Bhalla [90 , 91 ] in which MAPK increases expression of phosphatases, and particularly MKP-1, as part of the negative feedback control of their phosphorylation cascades. The well-known inhibitory effects of glucocorticoids on the positive feedback control components of the MAPK signaling cascades, e.g., phospholipase A2 for production of arachidonic acid and the prostaglandin-synthesizing system [82 ], may also play an important role. ERK1/2 stabilizes MKP-1 as well as increases in its mRNA level but at a rate slower than the MAPK activation of the positive feedback system [91 ]. Increased expression of MKP-1 may be related to the ability of the signaling cascade to respond to further stimulation rather than to acute control of the cascade [91 ]. If stabilizing and increasing transcription of MKP-1 rapidly should prove to be major functions of glucocorticoids, then the need to administer it before or simultaneously with the exposure to PAMPs becomes important and could control subsequent activation of the latter’s receptors.

The similarity of lethal outcomes obtained with S. aureus in ADX and intact mice, with or without DEX (Table 2) , suggests that glucocorticoid action has little effect on the activated TLR-2 and/or an associated TLR signal transduction system. In addition, the finding that C3H/HeJ mice (Fig. 2 , lower panels) lacking TLR-4 respond in the same overall way as CF-1 mice toward antibiotic-potentiated DEX protection, whether they are challenged with live E. coli or S. aureus, further indicates that TLR-4 is also not particularly important to these effects. Alternatively, antibiotic killing could provide a bacterial component common to E. coli and S. aureus that does not function through the TLR-2 or TLR-4 receptors or interacts with another receptor-mediated signaling system that is affected by the action of glucocorticoid. The identity of such components is currently unclear, but they obviously provide a potential target for therapeutic control of the innate-immune system.


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ACKNOWLEDGEMENTS
 
We dedicate this paper to the memory of Dr. Hans Selye who pioneered the study of stress and adrenal function. Although there are several criticisms of his definition of the General Adaptation Syndrome, authors continue to renew it in a modernized way. We also owe a special thanks to Dr. David C. Morrison for his steadfast support and encouragement. We acknowledge with gratitude the able assistance of Qiao Xue. We are also grateful to Wendy M. Baker for secretarial assistance and to Richard A. Grabbe for assistance with graphical representations.

Received July 31, 2002; revised November 26, 2002; accepted November 27, 2002.


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