Regulation of Tumor Necrosis Factor Receptor Expression by Acid-Labile Interferon-α from AIDS Sera

Abstract

High levels of an unusual acid-labile interferon (IFN) alpha in sera of patients with human immunodeficiency virus (HIV) infection are associated with disease progression to acquired immunodeficiency syndrome (AIDS). Since IFNs have been shown to enhance the cytotoxic actions of tumor necrosis factor (TNF), a potent mediator of inflammation and cachexia, a study was undertaken to investigate whether the acid-labile IFN alpha produced in AIDS can regulate TNF receptor expression. The expression of TNF receptors was determined by studying the interaction of [125I]TNF with cellular receptors. The results show the acid-labile IFN alpha present in AIDS sera is capable of inducing the expression of cellular receptors for TNF. The extent of induction of TNF receptors depends on the concentration of the acid-labile IFN alpha in the AIDS sera. There is no significant induction of TNF receptors when the AIDS sera are preneutralized with polyclonal anti-IFN alpha antibodies. It is also shown that the synthesis of TNF by peripheral blood monocytes (PBM) from patients with HIV infection is enhanced during the progression of HIV infection in vivo. Thus, the TNF system is activated in patients with HIV infection. This activation may be a contributing factor to some of the physiological disturbances including the wasting syndrome observed in AIDS.

An essential role for the interferon-inducible, double-stranded RNA-activated protein kinase PKR in the tumor necrosis factor-induced apoptosis in U937 cells.

“…On the other hand, it is possible that an aberrant up-regulation of TNF-a, for instance in a disease state, may ultimately lead to a prolonged expression of PKR, resulting in disjointed immune responses as well as activation of the apoptotic pathway. Thus, it is reasonable to postulate that the apoptotic destruction of T cells as documented in some AIDS patients can be partly accounted for by an inappropriate up-regulation of PKR caused by the activation of the TNF-a system commonly seen in HIV infection (19) It remains to be defined as to how TNF-a up-regulates PKR as described in this report. TNF-a is known to activate phospholipases A2, C, and D, serine/threonine phosphatases, 2'-5'-oligoadenylate synthetase to synthesize 2'-5'-oligoadenylate, (which in turn activates the RNase L that degrades viral mRNA), the PKC pathway that leads to phosphorylation of serine/threonine kinases, and the sphingomyelin pathway generating the second messenger ceramide, which in turn leads to activation of NF-KB (8).…”

Protein Kinase R Regulates Double-Stranded RNA Induction of TNF-α But Not IL-1β mRNA in Human Epithelial Cells

“…The wasting associated with HIV-infected individuals is due to chronic presence of TNF-␣ (59,60). Also, the morbidity and mortality of asthma are commonly associated with viral induction of proinflammatory cytokines such as TNF-␣, IL-1␤, IL-6, IL-8, GM-CSF, and RANTES (7,13,(61)(62)(63)(64)(65).…”

TNF and AIDS: Two sides of the same coin?

“…"-'3 Lau et a1. 14,15 have shown that an acid labile IFN-a present in AIDS patients' sera is capable of inducing the expression of cellular TNF receptors, in a concentration-dependent manner. Taking this into account, it may be suggested that this cytokine could decrease the serum concentration of TNF by an augmentation of the serum sTNFRs levels.…”