The proinflammatory cytokines interleukin 1 IL-1 , interleukin 6 IL-6 and the tumor necrosis factor alpha TNF as well as the antiinflammatory cytokines interleukin 1 receptor antagonist IL-1ra and interleukin 10 IL have been most investigated for their pyrogenic or antipyretic action.
The experimental evidence demonstrating the role of these secreted proteins in modulating the fever response is as follows: 1 association between cytokine levels in serum and CSF and fever; 2 finding of the presence of cytokine receptors on various cell types in the brain and demonstration of the effects of pharmacological application of cytokines and of their neutralizing antibodies on the fever response; 3 fever studies on cytokine- and cytokine receptor- transgenic models.
Studies on the peripheral and the central action of cytokines demonstrated that peripheral cytokines can communicate with the brain in several ways including stimulation of afferent neuronal pathways and induction of the synthesis of a non cytokine pyrogen, i. PGE2, in endothelial cells in the periphery and in the brain. The Murphy study used rabbit EP with pIs in the 5. In fact, each pyrogenic peak with an acidic pI coincided with LAF activity.
Subsequent reports supported that concept [ 15—18 ]. We continued to study the nonpyrogenic biologic activities of EP through each stage of purification, confirming the molecular heterogeneity of EP and LAF [ 19 ]. Other products of activated macrophages with lymphocyte-activating properties were described; these factors, along with EP, LEM, and LAF, were incorporated into the interleukin nomenclature.
Although the factors were designated interleukin-1 IL-1 , it was unclear at the time whether they represented a single molecule or several different molecules; at least four different pI values and several molecular weights were ascribed to EP before the term IL-1 was introduced.
A rapid expansion of studies on IL-1, with the use of in vitro lymphocyte assays, took place reviewed in [ 20 ]. However, such studies, including chemical characterization, had been done 5—10 years earlier in the case of EP [ 5 , 8 , 21 , 22 ].
It was not until the cloning of mouse IL-1 [ 23 ] and human IL-1 [ 24 ] in that the molecular heterogeneity was resolved. Both IL-1s were first synthesized as precursors with molecular weights of 31, but without signal peptides. Each had different primary sequences. What explained the 38,molecular-weight EP? The realization that IL-1 possessed a broad spectrum of biologic activities involving the pathogenesis of acute-phase responses spread rapidly, with confirmation of earlier studies on EP and LEM.
Experiments with recombinant IL-1 discussed below have demonstrated that IL-1 indeed causes fever [ 26 ] and mediates many components of the acute-phase response. It may be more appropriate to consider these polypeptides as a special class of substances called cytokines and to denote those cytokines that are intrinsically pyrogenic as EPs or pyrogenic cytokines to differentiate them from other cytokines that are not intrinsically pyrogenic.
The intravenous route produces a rapid onset of fever, within 30 min, whereas subcutaneous administration takes slightly longer. The term EP today often refers to IL-1, because IL-1 was the first to be endogenously purified and characterized as both a pyrogenic and lymphocyte-activating molecule. IL-6 and TNF also possess these biologic properties; however, these have biologic and physical characteristics that clearly distinguish them from IL For example, in the rabbit assay, to fold more IL-6 than IL-1 is needed for a monophasic fever [ 27 ].
Thus, purified EP could not have been IL-6, because the specific activity was too high. In addition, the pI of IL-6 is 6. In the days before the isolation and purification of EP, most experiments were, in fact, carried out with a mixture of pyrogenic cytokines, and certainly the crude leukocyte supernatants and serum from febrile animals contained such a mixture of IL-1, TNF, and IL From a clinical standpoint, during most febrile diseases, several pyrogenic cytokines are produced and likely contribute to the febrile response.
These now include a family of cytokines that use the cell signaling apparatus gp Cytokines using this receptor are pyrogenic, and currently they include IL-6, IL, oncostatin M, ciliary neurotrophic factor [ 29 ], cardiotropin-1, and leukemic inhibitory factor. Although fever is primarily associated with infectious diseases, the febrile response is, in fact, a prominent component of many inflammatory and immunologically mediated diseases and frequently accompanies certain malignancies.
However, fever is hardly an isolated event. Increases in the total and relative numbers of circulating young neutrophils often occur. In addition, many febrile illnesses are accompanied by an increase in the synthesis of a variety of hepatic acute-phase proteins. These include antiproteases, haptoglobin, several complement components, fibrinogen, ceruloplasmin, and ferritin.
There can also be or fold increases in special acutephase proteins such as C-reactive protein and serum amyloid A protein. The dramatic increase in the rate of synthesis of these proteins occurs despite the fact that hepatic albumin synthesis is markedly reduced; indeed, the host is often in negative nitrogen balance.
In general, the onset of fever accompanied by these hematologic and metabolic changes is frequently referred to as the acute-phase response. The acute-phase response is a systemic, generalized reaction, although most disease processes that induce it are localized. There has been considerable speculation that the role of acute-phase proteins is to help contain pathogens and their toxins and to inactivate microbial proteases and highly reactive O 2 metabolites.
More than one leukocyte product is now identified as mediating acute-phase hepatic protein synthesis. These latter proteins include lipoprotein lipase, albumin, and cytochrome P The ability of these cytokines to suppress gene expression for these commonly produced molecules accounts, in part, for the altered lipid and drug metabolism states observed in patients with acute or chronic infections or inflammatory diseases.
There are still no data demonstrating that EPs produced in peripheral tissues and reaching the brain via the systemic circulation actually penetrate the blood-brain barrier and enter the brain tissue itself.
These sites, called the circumventricular organs or organum vasculosum laminae terminalis OVLT , possess little if any blood-brain barrier. Thus, it is likely that endothelial cells lining the OVLT either offer no resistance to the movement of EPs into the brain or release arachidonic acid metabolites themselves when they encounter EPs from the circulation. Alternatively, prostaglandin E 2 PGE 2 and other prostaglandins may be produced by the endothelial cells, which, in turn, induce a neurotransmitter-like substance that acts to raise the set-point.
This explanation is actually likely, since prostaglandins are not suitable as neurotransmitters. PGE 2 is known to increase levels of cyclic AMP, which has neurotransmitter properties in brain tissue and has been implicated in fever [ 31a ]. Figure 1 is a scheme showing the likely events leading to the synthesis of EPs and their ability to produce fever. Scheme for pathogenesis of fever. Although these two arachidonate metabolites increase blood flow, IL-1 and TNF also orchestrate a cascade of cellular and biochemical events that lead to vascular congestion, clot formation, and cellular infiltration.
One way in which IL-1 and TNF initiate these events is by stimulating the plasma membrane of endothelial cells so that neutrophils, monocytes, and lymphocytes adhere avidly to them [ 33 ].
This molecule interacts with the leukocyte-glycoprotein complex designated leukocyte function antigen. IL and TNF-induced increases in procoagulant activity on the endothelial cell surface serve to increase coagulation. These events lead to activation of factor VIII and thrombin in the initiation of clotting. Taken together, these effects of IL-1 and TNF lead to decreased blood flow in vessels and increased accumulation of leukocytes and platelets.
Since IL-1 is a stimulator of thromboxane release from neutrophils, activated neutrophils adhering to endothelial cells are likely to increase platelet aggregation.
Thromboxane release from adherent neutrophils may also contribute to fever, since thromboxane levels in the third cerebral ventricle rise with the early increase in EP-mediated fever [ 35 ]. IL-1 stimulates the release of platelet-activating factor from endothelial cells [ 36 ], which, in turn, may affect the subsequent release of arachidonic acid metabolites. Several groups of investigators have purified IL-1 to homogeneity, using T cell stimulation as a biologic marker, and have shown that the isolated material produces typical EP fever.
In an independent study, Van Damme et al. Hanson and Murphy [ 39 ] purified rabbit IL-1 with a pI of 5 to a single band and showed that it produced typical EP fever. Other investigators demonstrated that purified human monocyte IL-1 with a pI of 7 evoked fever in endotoxin-resistant mice [ 40 ].
Because IL-1 and other recombinant cytokines are expressed in Escherichia coli , considerable caution must be used to exclude the involvement of contaminating endotoxin in the isolated product. Moreover, the EP fever produced by such a preparation is unaffected by polymyxin B, which blocks the pyrogenic effect of E.
In humans, IL-1 appears to be the most potent cytokine. Although the systemic effects of IL-1 have been studied in animals, there are now data on the effects of and sensitivity to IL-1 in humans. The febrile response increased in magnitude with increasing doses [ 46—48 ], and chills and fever were abated with indomethacin treatment [ 49 ].
These results suggest that the hypotension is probably due to induction of NO, and elevated levels of serum nitrate have been measured in patients with ILinduced hypotension [ 48 ]. In addition, there were increases in adrenocorticotropic hormone and thyroid-stimulating hormone but a decrease in testosterone [ 48 ].
No changes were observed in coagulation parameters, such as prothrombin time, partial thromboplastin time, or fibrinogen degradation products. Not unexpectedly, IL-1 infusion into humans significantly increased circulating IL-6 levels in a dose-dependent fashion [ 48 ]. These elevations in IL-6 are associated with a rise in C-reactive protein and a decrease in albumin. TNF is a macrophage product that has a direct cytotoxic effect on certain tumor cells. Human TNF has been cloned and shares significant amino acid homology with another macrophage product, cachectin [ 57 ].
Originally, cachectin was characterized as an endotoxin-induced macrophage product that mediated severe weight loss, in part through its ability to inhibit lipoprotein lipase. TNF also shares many biologic properties with IL For example, recombinant IL-1 and recombinant TNF both stimulate synovial cell production of PGE and collagenase, endothelial cell procoagulant activity, and release of platelet-activating factor.
Both molecules are cytotoxic for certain tumor cells, and both induce hepatic acute-phase proteins. In addition, lymphocyte activation, cytotoxicity for insulin-producing beta cells, and release of adrenocorticotropic hormone are also shared properties of both IL-1 and TNF.
It is remarkable, therefore, that the amino acid sequences of TNF and either form of IL-1 share no discernible regions of significant homology. The rapid rise in body temperature that occurs in rabbits after intravenous injection of TNF is indistinguishable from that produced by either form of recombinant IL The fever curves and peak temperature elevations are nearly superimposable.
The fever induced in these humans is rapid and is associated with generalized malaise and joint pain. Incubation of TNF with either human blood monocytes or cultured human endothelial cells induces IL-1 in vitro [ 28 , 58 ].
The induction of IL-1 by TNF takes place in the presence of polymyxin B, which blocks endotoxin effects in a variety of assays. Thus, it is unlikely that endotoxin accounts for these biologic properties of TNF. TNF is also an endogenous inducer of IL This property implicates TNF in the pathogenesis of endotoxin fever, since endotoxin stimulates large amounts of TNF in vivo. At present, it is clear that the pathogenesis of fever requires consideration of both IL-1 and TNF levels following the injection of a variety of exogenous pyrogens.
Recombinant lymphotoxin also manifests EP activity and induces IL-1 both in vivo and in vitro unpublished data. TNF has also been crystallized, revealing that this molecule is normally found as a trimer in nature. This explains the various molecular weights reported for TNF bioactivity in years that preceded its molecular cloning. The monomer of TNF has a molecular weight of 17,, but unlike IL-1, this monomer does not contain any methionine.
The tertiary structure of TNF in the trimer form appears to be critical for biologic activity. This discrepancy has been reported in body fluids for several disease processes. The biologic activity of TNF is most often measured by its cytotoxic effects on a number of susceptible cells. Two structurally distinct polypeptides form the external part of the TNF receptor. The TNF trimer cross-links these two receptor molecules, and this cross-linking triggers signal transduction [ 62 , 63 ].
Antibodies to the TNF receptor polypeptides have been produced, and these antibodies signal TNF biologic activity when cross-linked by anti-F ab' 2.
On close examination, this IFN had little intrinsic antiviral activity but rather possessed other biologic activities. This molecule was cloned, and its entire cDNA-derived amino acid sequence was published in [ 64 ]. Other investigators had isolated a polypeptide that stimulated B cell growth, hybridoma growth, and hepatic acute-phase protein synthesis. The recombinant molecule also possessed the acute-phase protein-inducing properties [ 66 ], and the molecule was renamed IL Later, it was shown that IL-6 produced typical EP fever when injected into rabbits and that there was a positive correlation in humans with burns between fever and IL-6 levels [ 67 , 68 ].
In general, IL-6 fever in rabbits requires concentrations between and fold greater than that required for IL There are no known studies of IL-6 administration in humans.
There have been multiple reports of IL-6 levels in a variety of human diseases and in various human body fluids such as plasma, cerebrospinal fluid, and joint fluids. The acute-phase-inducing properties of IL-6 may be viewed as antiinflammatory, since most acute-phase hepatic proteins are either oxygen scavengers or antiproteases. One of the most potent proinflammatory properties of IL-1 is its ability to induce gene expression for cyclooxygenase, thus resulting in large amounts of prostaglandin synthesis.
IL-6 does not stimulate PGE formation through increased cyclooxygenase gene expression [ 69a ]. The fever due to IL-6 is reduced by cyclooxygenase inhibitors, suggesting that cyclooxygenase products are induced by IL-6; however, a clear distinction must be made between the ability of IL-6 to transiently induce prostaglandins from cell surface signal transduction and induction of the cyclooxygenase genes, resulting in prolonged days prostaglandin synthesis. IL-1, TNF, and other cytokines are often produced by the same cells and induced by the same stimulators; all possess high specific activities at the picogram- or nanogram-per-milliliter level in a variety of biologic assays.
The case for the multiple biologic activities of IL-1 has also existed with regard to the IFNs, which were initially described as antiviral substances. IFNs were the first cytokines administered to humans. Increase in body temperature is thought to help defend the body against infection by stimulating the activity of the immune cells. Reference s : 1 Dinarello, C. The human body is capable of regulating growth and energy balance through various feedback mechanisms.
Get to know the events of absorptive and post-absorptive states. This tutorial also describes the endocrine and neural control of compounds such as insulin and glucagon. It also deals with the regulation of growth, heat loss, and heat gain.
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