Serum TNF

TNF is produced and secreted by activated cells within minutes following contact with LPS, reaching peak levels at 90-120 minutes after the admnistration of Escherichia coli endotoxin in human volunteers (M27). Van Deventer et al. (D15) could not detect serum TNF levels during experimental endotoxemia. Even during continuous intravenous administration of recombinant TNF (rTNF), serum TNF rapidly becomes undetectable (M27). It has been proposed that circulating soluble TNF receptors (sTNF-Rs) may be an important down-regulating mechanism (G10). 

The biologic activity of TNF-ct is mediated by binding of soluble or membrane-bound TNF- trimers to cell-surface TNF- receptors. Infliximab binds to soluble TNF- trimers with high affinity, preventing the cytokine from binding to its receptors. Serum TNF- concentrations may actually increase because binding to infliximab slows TNF-rt clearance. Infliximab also binds to membrane-bound TNF-a and neutralizes its activity. Furthermore, the Fc portion of human IgGl... 

Fig. 12.8 (A) Dose-response relationship for adalimumab following singledose administration in patients with rheumatoid arthritis. (Figure produced from data reported in [78]). (B) Simulated suppression of serum TNF-a following single-dose administration of adalimumab.

In general, a review of the available literature for arili-TN F-a biologies reflects that, at steady state, the highest proportion of the observed response (maximum therapeutic effect) appears to occur in patients with steady-state semm concentrations ranging between 1 to 10 pg/mL, independent of the compound. This is anticipated since the reported affinities of the anti-TN l -a biologies to TNF-a are comparable (etanercept, 65 pM adalimumab, 78 pM and infliximab, 100 pM). Comparable steady-state serum trough concentrations of the drugs are therefore necessary for a >90% suppression of serum TNF-a. 

Can, C., Demirci, B., Uysal, A., Akcay, Y.D., and Kocay, S. 2003. Contradictory effects of chlorpromazine on endothelial cells in a rat model of endotoxic shock in association with its actions on serum TNF- levels and antioxidant enzyme activities. Pharmacologic Res 48(3) 223-230. 

A role for the release of Wolbachia bacterial endosym-bionts has been suggested in the pathogenesis of the Mazzotti reaction (SEDA-26, 345). There was a good correlation between Wolbachia DNA, serum TNF-alfa, and the antibacterial peptides calprotectin and calgranu-lin after treatment with ivermectin or diethylcarbamazine, supporting a role for Wolbachia products in mediating these inflammatory responses (27). 

TNF expression or protein production has been demonstrated in many cancer cell lines and biopsies. For example, in ovarian and breast cancers, TNF mRNA or protein has been found in 50% to 70% of the tumors studied. Serum TNF and sTNFR levels are raised in a wide range of malignancies, and their measurement may be useful in follow-up studies. 

Barlan IB, Basaran MM, Bakir M, et al. Serum TNF-a, sCD8 and sIL-2R levels in childhood tuberculosis. Infection 1995 23 237-9. 

Tuncer AM, Hicsonmez G, Gumruk F, et al. Serum TNF-a, gamma-INF, G-CSF levels in neutropenic children with acute leukemia treated with short-course, high-dose methylprednisolone. Leuk Res 1996 20 265-9. 

Mussi A, Bonifati C, Carducci M, et al. Serum TNF-alpha levels correlate with disease severity and are reduced by effective therapy in plaque-type psoriasis. J Biol Regul Homeost Agents 1997 11 115-118. 

Serum TNF-a levels were increased, although nonsignificantly, in male adult older C57BL/6J mice... 

Serum TNF-a levels were increased, although nonsignificantly, in mice that received 10 pg mela-tonin/ml drinking water (only during the night hours from 18.00 and 9.00) supplementation (Chen et al. 1999). 

Ayala A, Perrin MM, Meldrum DR, et al. Hemorrhage induces an increase in serum TNF which is not associated with increased levels of endotoxin. Cytokine 1990 2 170-174. 

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