Table 2.
Proinflammatory Cytokines Implicated in IGF-Resistance
| Ligands | (Synonyms) | F.W.1 | Structure | |
|---|---|---|---|---|
| TNFα | (Cachectin) | 17.3 | Trimer active form | |
| IL-1β | 17.4 | Monomeric active form | ||
| Receptors | Notes | |||
| TNF-R1 | (p55/p60, CD120a antigen) |
h/m 48/48 | Homodimer (ligand recruitment of 3 dimers) |
Murine receptor binds murine and human TNFα |
| TNF-R2 | (h/m p75/p80, CD120b antigen) |
h/m 46/48 | Homodimer (ligand recruitment of 3 dimers) |
Murine receptor binds only murine TNFα |
| IL-1R-1 | (p80, CD121a antigen) |
65 | Heterodimer with IL-1RAcP | Member of the toll-like receptor family |
| IL-1RacP | 63 | Heterodimer with IL-1R-1/2 | ||
| Natural Antagonists | Notes | |||
| sTNF-R2 | 25 | Sequesters TNFα to temper activity | ||
| (Etanercept2) | 150 | Designed antagonist | ||
| IL-1ra | (IRAP) | 17 | Competes with IL-1β to temper receptor activation | |
| IL-1R-2 | (IL-1RII, CD121b antigen) |
44 | As a receptor, forms a heterodimer with IL-1RacP, may sequester IL-1RacP to reduce IL-1β activity | |
 | ||||
Controlling cytokine activity is critical for wellness and regulating inflammatory responses. Most cytokine receptors are present at 100–1,000 receptors per cell, or at about 10% the level of hormone receptors. TNF-R1 and TNF-R2 have Kds of 0.02 and 0.4 nM, respectively. Concentrations of circulating ligand, such as TNFα, are generally less than 0.0005nM(0.009ng/ml). Similarly the IL-1R-1 and IL-1R-2 bind with affinities all less than 3 nM. Similar to TNFα, serum levels in healthy individuals of IL-1β are below the Kd of the receptors (example; IL-1β is 0.0008 ng/ml (0.00005 nM) in serum of adult humans [167]). These facts indicate that receptor activation parallels changes in ligand availability. During inflammation, circulating levels of the cytokines increase to concentrations adequate to activate cellular events. Although proinflammatory cytokine concentrations are below receptor Kds, additional controls exist, similar to the IGF system. Proinflammatory cytokines have both decoy receptors and soluble negative regulators that control the amount of active ‘free’ cytokine in the extracellular space.
Human - h, mouse - m. Size of monomeric forms based on amino acid composition of the mature protein (Swiss-Prot; ExPASy).
Etanercept consists of two extracellular binding domains of TNF-R2 linked to the Fc portion of human IgG1 (weight approximate).