Interleukin-1 beta (IL-1 beta)-converting enzyme cleaves the IL-1 beta precursor to mature IL-1 beta, an important mediator of inflammation. The identification of the enzyme as a unique cysteine protease and the design of potent peptide aldehyde inhibitors are described. Purification and cloning of the complementary DNA indicates that IL-1 beta-converting enzyme is composed of two nonidentical subunits that are derived from a single proenzyme, possibly by autoproteolysis. Selective inhibition of the enzyme in human blood monocytes blocks production of mature IL-1 beta, indicating that it is a potential therapeutic target.

A novel heterodimeric cysteine protease is required for interleukin-1 beta processing in monocytes.

Interleukin-1 and interleukin-1 antagonism.

Turnbull, Andrew V., and Catherine L. Rivier. Regulation of the Hypothalamic-Pituitary-Adrenal Axis by Cytokines: Actions and Mechanisms of Action. Physiol. Rev. 79: 1–71, 1999. — Glucocorticoids a...

Regulation of the Hypothalamic-Pituitary-Adrenal Axis by Cytokines: Actions and Mechanisms of Action

The brain and immune system form a bidirectional communication network in which the immune system operates as a diffuse sense organ, informing the brain about events in the body. This allows the activation of immune cells to produce physiological, behavioral, affective, and cognitive changes that are collectively called sickness, which function to promote recuperation. Fight-flight evolved later and coopted this immune-brain circuitry both because many of the needs of fight-flight were met by this circuitry and this cooptation allowed the immune system to respond to potential injury in anticipatory fashion. Many sequelae of exposure to stressors can be understood from this view and can take on the role of adaptive responses rather than pathological manifestations. Finally, it is argued that activation of immune-brain pathways is important for understanding diverse phenomena related to stress such as depression and suppression of specific immunity.

Cytokines for psychologists: implications of bidirectional immune-to-brain communication for understanding behavior, mood, and cognition.

Three interleukin-1 inhibitors have been purified to homogeneity from medium conditioned by human monocytes. Partial sequence analysis and digestion with N-glycanase indicate that these are glycosylation forms of a single protein. The protein binds to the interleukin-1 receptor but has no interleukin-1-like activity, even at very high concentrations, and is therefore a pure receptor antagonist.

Interleukin-1 receptor antagonist activity of a human interleukin-1 inhibitor

Human monocytes induced with adherent IgG secrete an interleukin-1 receptor antagonist which could be important for the in vivo regulation of IL-1 activity. A complementary DNA for this molecule has been isolated from a human monocyte library. Analysis of monocyte RNA indicates that the gene is transcriptionally regulated. The sequence of the receptor antagonist indicates that it is structurally similar to IL-1 beta. Expression of the cDNA in Escherichia coli yields IL-1 receptor antagonist activity.

Primary structure and functional expression from complementary DNA of a human interleukin-1 receptor antagonist

Compounds are disclosed having the general formula R1-X-R2, wherein R1 and R2 are biologically active groups, at least one of which is polypeptidic. X is a non-peptidic polymeric group. R1 and R2 may be the same or different. Preferred R1 and R2 groups are interleukin-1 receptor antagonist, 30kDa TNF inhibitor, interleukin-2 receptors and CR1 and muteins thereof. Also included are site selectively modified interleukin-1 receptor antagonist and 30kDa TNF inhibitor.

Pegylation of polypeptides

Rabbit interleukin-1 receptor antagonist. Cloning, expression, functional characterization, and regulation during intestinal inflammation.

The present invention provides nucleic acid molecules encoding a 30kDa TNF inhibitor or a fragment thereof having at least one non-native cysteine residue at the N-terminus, C-terminus, residue 14, or residue 15.

Nucleic acids encoding TNF inhibitor and method of production

At least two substantially purified tumor necrosis factor (TNF) inhibitors are disclosed which are glycoproteins that are active against TNF. The isolation of 30kDa and 40KDa TNF inhibitors from urine is disclosed. The deglycosylated form of the 30kDa TNF inhibitor and 40kDa TNF inhibitor are described as being active against TNF. The 40kDa TNF inhibitor is active against both TNF alpha and TNF beta. The amino acid sequence of the 30kDa TNF inhibitor and the 40kDa TNF inhibitor are disclosed. Methods for isolating the TNF inhibitors from human U937 cell medium are also described.

Michael T Brewer

Papers

Primary structure and functional expression from complementary DNA of a human interleukin-1 receptor antagonist

Pegylation of polypeptides

Rabbit interleukin-1 receptor antagonist. Cloning, expression, functional characterization, and regulation during intestinal inflammation.

Nucleic acids encoding TNF inhibitor and method of production

Tumor necrosis factor (tnf) inhibitor and use thereof