Fever interleukin

Fever is the most common manifestation. The thermoregulatory centre in the hypothalamus regulates body temperature and this can be affected by endotoxins (heat-stable lipopolysaccharides) of Gram-negative bacteria and also by a monokine secreted by monocytes and macrophages called interleukin-1 (IL-1) which is also termed endogenous pyrogen. Antibody production and T-cell proliferation have been shown to be enhanced at elevated body temperatures and thus are beneficial effects of fever. 

Denileukin diftitox is a combination of the active sections of interleukin 2 and diphtheria toxin. It binds to high-affinity interleukin 2 receptors on the cancer cell (and other cells), and the toxin portion of the molecule inhibits protein synthesis to result in cell death. The pharmacokinetics of denileukin diftitox are best described by a two-compartment model, with an a half-life of 2 to 5 minutes and a terminal half-life of 70 to 80 minutes. Denileukin diftitox is used for the treatment of persistent or recurrent cutaneous T-cell lymphoma whose cells express the CD25 receptor. Side effects include vascular leak syndrome, fevers/chills, hypersensitivity reactions, hypotension, anorexia, diarrhea, and nausea and vomiting. 

C5, Cannon, J. G Tompkins, R. G., and Gelfland, J. A., Circulating interleukin-1 and tumor necrosis factor in septic shock and experimental endotoxin fever. J. Infect. Dis. 161, 79-84 (1990). 

E10. Engel, A Kern, W. V., Miirdter, G., and Kern, P Kinetics and correlation with body temperature of circulating interleukin-6, interleukin-8, tumor necrosis factor alpha and interleukin-1 beta in patients with fever and neutropenia. Infection 22, 160-164 (1994). 

Horai, R. et al., Production of mice deficient in genes for interleukin (IL)-la, IL-ip, and IL-1 receptor antagonist shows that IL-lp is crucial in turpentine-induced fever development and glucocorticoid secretion, J. Exp. Med., 187, 1463, 1998. 

Pyrogens (e.g., bacterial matter) elevate—probably through mediation by prostaglandins (p. 196) and interleukin-1—the set point of the hypothalamic temperature controller (B2). The body responds by restricting heat loss (cutaneous vasoconstriction chills) and by elevating heat production (shivering), in order to adjust to the new set point (fever). Antipyretics such as acetaminophen and ASA (p. 198) return the set point to its normal level (B2) and thus bring about a defervescence. 

In many instances the influence of pyrogens on body temperature is indirect, e.g. entry of endotoxin into the bloodstream stimulates the production of interleukin 1 (IL-1 Chapter 5) by macrophages. It is the IL-1 that directly initiates the fever response (hence its alternative name, endogenous pyrogen ). 

Aldesleukin is a recombinant form of human Interleukin-2 (IL-2). It has been approved for the treatment of malignant melanoma and renal cell cancer. The medicine is administered every 8 hours by a 15-minute intravenous infusion for a maximum of 14 doses. Adverse reactions include hypo- and hypertension, gastrointestinal disturbances, fever, fatigue, lethargy, joint pain, headache. Cardiovascular problems may occur. 

The salicylates are also potent antipyretic agents, with the exception of diflunisal, which is only weakly active. Aspirin acts at two distinct but related sites. It decreases prostaglandin-induced fever in response to pyrogens and induces a decrease in interleukin-1 modulation of the hypothalamic control of body temperature. Thus, the hypothalamic control of body temperature returns, vasodilation occurs, heat dissipates, and fever decreases. Other uses of aspirin include inhibition of platelet aggregation via inhibition of thromboxanes, which has been shown to decrease the incidence of blood clots, myocardial infarction, and transient ischemic attacks. 

Interleukin-1 was originally discovered as a factor that induced fever, caused damage to joints and regulated bone marrow cells and lymphocytes, it was given several different names by various investigators. Later, the presence of two distinct proteins, IL-la and IL-1 (3, was confirmed, which belong to a family of cytokines, the... 

ThEF-a (tumour necrosis factor alpha) is the best known member of a group of pro-inflammatory cytokines, including interleukin-1 (IL-1) and interleukin-6 (IL-6), collectively responsible for the fever and inflammation associated with infections and serious disease. 

Fever is common a mechanism is the release of interleukin-1 by leucocytes into the circulation which acts on receptors in the hypothalamic thermoregulatory centre, releasing prostaglandin Ej. 

Endotoxin pyrogen induces fever by an indirect process. On entry into the circulatory system, endotoxin is bound to LPS-binding protein (LPB) that transports it to receptor cells in the reticuloendothelial system. The main target cells are circulating mononuclear cells, which produce proinflammatory cytokines such as interleukin-1 (IL-1), interleukin-6 (IL-6), and tumor necrosis factor-a (TNFot). These cytokines are involved in acute and chronic inflammation, induce fever, and modulate the host s response to bacterial infection. ° ... 

Negussie Y, Remick DG, DeForge LE, Kunkel SL, Eynon A, Griffin GE. Detection of plasma tumor necrosis factor, interleukins 6, and 8 during the Jarisch-Herxheimer reaction of relapsing fever. J Exp Med 1992 175(5) 1207-12. 

In patients with ovarian cancer, the combination of inter-leukin-3 with high-dose carboplatin was poorly tolerated severe fever, malaise, protracted nausea, vomiting, severe hypotension, and nephrotoxicity required withdrawal of interleukin-3 in 60% of patients when interleukin-3 was given only 24 hours after high-dose carboplatin (18). 

Oxaliplatin is generally well tolerated. Some patients develop fever, which appears to be related to a transient increase in cytokines, particnlarly interlenkin-6 and tnmor necrosis factor alfa. In one stndy the oxaliplatin-induced increase in body temperatnre correlated with a marked increase in interlenkin-6 sernm concentrations (peak 133 pg/ml) (251). Interlenkin-6 is a proinflamma-tory cytokine, which stimnlates acnte phase proteins and B lymphocytes. Premedication with metamizol, dexamethasone, and clarithromycin, which interferes with interleukin-6, did not prevent the fever. The roles of interleukin-6 and tumor necrosis factor alfa in the development of fever is strengthened by the observation that their serum concentrations fell during resolution of the fever (252). 

Of 52 patients with colorectal cancer treated with a median of six 3-weekly cycles of raltitrexed 1.5-3.0 mg/m combined with oral carmofur 300-400 mg/m on cycle days 2-14, 39 had a fever on days 2-9 after receiving raltitrexed, 49 had fatigue, and 49 had a raised serum C-reactive protein concentration without a documented infection (6). Median concentrations of C-reactive protein, interleukin-6, interleukm-8, and tumor necrosis factor-alfa were higher 7 days after raltitrexed or raltitrexed + carmofur than at baseline. The authors suggested that patients with colorectal cancer treated with raltitrexed may develop drug-related systemic inflammation, which may be difficult to distinguish from infection. 

---