Signalling via NF- B

The assembly of the two complexes at the TNF1R results in polyubiquitylation of RIP1 by TRAF2 (Figure 16.4). The polyubiquitin chains (K63 type) thus formed serve as docking sites for the TAB2/TAB3/TAK1 complex and for NEMO/ IKK /IKK . From here on the series of events is similar to that described

for the activation of NF- B by TLR4 in response to LPS (page 460). TAK1 phosphorylates IKK causing its activation and subsequent phosphorylation of I B , which after ubiquitylation is degraded by the proteasome. The dissociation of I B reveals a targeting signal on the NF- B complex that directs it to the nucleus.42 Here it promotes transcription of the genes for VCAM-1, ICAM, etc, (see also figure 15.3, page 456).

TNF- (but also histamine, IL-1 , LPS, thrombin, etc.), induces a short-lived upregulation of VCAM-1 and ICAM-1 and also of E- and P-selectins on vascular endothelial cells. P-selectin, stored in specialized secretory granules, is rapidly transferred to the plasma membrane. Expression of E-selectin, ICAM-1, and VCAM-1 occurs more slowly and then persists for a few days. The increased density of these adhesion molecules on the surface of endothelial cells enhances their ‘avidity’ (the product, density affinity) for leukocytes.

The pathway triggered by TNFis self-limiting because NF- B also enhances the expression of I B which initiates a negative feedback loop that attenuates the TNF signal (Figure 16.4). This secures the return to the basal expression of VCAM- 1 and ICAM-1. Their appearance at the cell surface is therefore transient, allowing termination of the inflammatory response. Without this, the influx of leukocytes would be prolonged, causing chronic tissue damage, as occurs in the formation of ulcers.

Control of inflammation by apoptotic neutrophils and T cells. The final resolution of the inflammatory response not only requires that transcription of inflammatory mediators ceases: they must also be eliminated from the tissues. Massive apoptosis of neutrophils and T cells is a hallmark of the termination of inflammation. Whilst dying, and before being eliminated by macrophages or other tissue cells, these leukocytes express high levels of the chemokine

receptor CCR5. This also acts as a sink that sequesters the chemokines CCL3, -4, and 5. Mice lacking CCR5 manifest a prolonged presence of inflammatory mediators in their tissues.45

Signalling via p38 and JNK

TRAF2 and RIP serve as docking platforms for a number of MAP3Kinases (NIK, MEKK1, ASK1 for RAF2 and MEKK3, TAK1 for RIP) all capable of activating the stress kinases p38 and JNK. In turn these phosphorylate transcription factors, thereby activating c-Jun and ATF2 (AP-1 complex).

TNFand cachexia.

Prolonged exposure to low concentrations of TNFcauses the wasting syndrome cachexia (from the Greek kakos, bad, and hexis, constitution). Indeed, cachectin, the mediator responsible for cachexia in mice exposed to trypanosome infection, has been identified as TNF- .43 Cancer patients suffer from cachexia, manifested as anorexia, early satiety, muscle wasting, weight loss, fatigue, and impaired immune response. Other inflammatory mediators that are involved in cachexia are IL-1, IL-6, and IFN- . These are either secreted by the tumour alone or in concert with host-derived factors.44 They exert their effect directly on muscle metabolism, causing wasting of tissue, and indirectly by modifying neurotransmitter release in the hypothalamus (changing appetite, taste, and social behaviour).