Activation Pathways of Endothelial Cells in Chronic Inflammation

Activation of endothelial cells leads to changes in endothelial cell properties such as loss of vascular integrity, expression of adhesion molecules, antithrombotic to prothrombotic phe-notype changes, cytokine production and the upregulation of HLA molecules. All these diverse effects can be attributed to the activation of transcription factors [44]. Of the presently known transcription factors, NFkB is believed to be one of the most important in the regulation of endothelial cell activation. After a stimulus at the cell surface which is caused by e.g.

Figure 7.3. Schematic representation of some of the intracellular signal transduction pathways of cytokine receptor signalling. Interleukin (IL)-1 and TNFa, among others, induce cell activation via the NFkB pathway, although their respective signal transduction routes upstream of the NFkB system differ significantly. On interaction with their receptors, NFxB-inducible kinase (NIK) is activated resulting in IxB-kinase (IKK) phosphorylation. As a result, IxBa is phosphorylated, thereby becoming a substrate for ubiquitination and proteasome-mediated degradation. The released p50/p65 NFkB complex translocates to the nucleus, which results in the expression of inflammatory genes. The JAK/STAT route can be activated by cytokine (e.g. IL-6, IL-10 or IL-15) binding to their receptors. JAK phosphorylation is followed by phosphorylation of receptor subunits which function as a docking site for STAT molecules. Phosphorylated STAT molecules subsequently dimerize, translocate to the nucleus and modulate gene transcription.

Figure 7.3. Schematic representation of some of the intracellular signal transduction pathways of cytokine receptor signalling. Interleukin (IL)-1 and TNFa, among others, induce cell activation via the NFkB pathway, although their respective signal transduction routes upstream of the NFkB system differ significantly. On interaction with their receptors, NFxB-inducible kinase (NIK) is activated resulting in IxB-kinase (IKK) phosphorylation. As a result, IxBa is phosphorylated, thereby becoming a substrate for ubiquitination and proteasome-mediated degradation. The released p50/p65 NFkB complex translocates to the nucleus, which results in the expression of inflammatory genes. The JAK/STAT route can be activated by cytokine (e.g. IL-6, IL-10 or IL-15) binding to their receptors. JAK phosphorylation is followed by phosphorylation of receptor subunits which function as a docking site for STAT molecules. Phosphorylated STAT molecules subsequently dimerize, translocate to the nucleus and modulate gene transcription.

interaction between a cytokine (IL-1,TNFa) and its receptor, UV radiation, lipopolysaccha-ride (LPS) or oxidized low density lipoproteins (oxLDL), NFKB-inducible kinase (NIK) is activated, which in turn phosphorylates lKB-kinase-1 (IKK-1), and perhaps IKK-2. The IKK molecules phosphorylate the inhibitor of KB (IKB) at serine-residues, resulting in ubiquitina-tion and degradation of IKB by the proteasome machinery in the cell cytoplasm. The nuclear localization sequence (NLS) of the NFKB dimer then becomes exposed, after which the transcription factor travels to the nucleus and induces transcription of many pro-inflammatory genes (Figure 7.3) [45]. Since NFkB is a key component in the inflammation process, this important transcription factor is controlled by several autoregulatory loops. The expression of the inhibitory protein IKBa to which NFkB is bound in the cytoplasm, becomes upregulated when NFkB is activated, thereby repressing the transcription of VCAM-1 and E-selectin for instance [46]. Large quantities of NO produced by the inducible NO-synthase enzyme (iNOS) prevent further NFkB activation either by S-nitrosylation of cysteine 62 of the p50 subunit of NFkB or by stabilization of the inhibitory iKB-a protein [47,48]. As described above, the anti-apoptotic proteins Bcl-2, A20 and Bcl-xL play an important role in controlling inflammation, as well as in endothelial cell activation. This is partly due to their ability to inhibit NFkB activation in endothelial cells. In vitro, these proteins block the induction of proinflammatory genes such as cytokines, pro-coagulant and adhesion molecules, and hence serve as a regulatory mechanism to restrain activation and injury [49,50].

Class I and II cytokine receptors that do not have direct tyrosine kinase activity mediate signal transduction in cells via JAK (janus kinase) and STAT (signal transduction and activator of transcription) molecules. Among these are receptors for IL-15 and GM-CSF, cy-tokines involved in T cell recruitment to rheumatoid arthritis lesions and pro-angiogenic responses of endothelium, respectively [17]. Each cytokine activates a pre-defined set of JAKs through interaction between one of the receptor subunits and a JAK molecule. The JAKs then become activated by reciprocal transphosphorylation and in turn phosphorylate substrates such as receptor subunits (Figure 7.3). This creates a docking site for signalling molecules leading to subsequent signal transduction cascades. Downstream of JAK activation lies a variety of targets, including the low molecular weight G protein Ras and its targets PI3-ki-nase and the serine/threonine kinase Akt or protein kinase B. In parallel, members of a family of STAT transcription factors sharing a central DNA-binding domain, can become phos-phorylated. Their subsequent dimerization leads to nuclear localization and DNA-binding, although this is not sufficient for their transactivation. Through physical and functional interactions between STATs and other transcription factors gene transcription can take place to modulate cellular functions [51]. It has been reported that the c-Jun N-terminal kinase group of MAP kinases plays a role in endothelial cell signal transduction and activation upon exposure to inflammatory cytokines, in a manner similar to that described above. Due to space limitations, this will not be discussed further: a detailed description of the role of this regulatory pathway in various inflammatory conditions can be found in reference [52].

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Arthritis Joint Pain

Arthritis Joint Pain

Arthritis is a general term which is commonly associated with a number of painful conditions affecting the joints and bones. The term arthritis literally translates to joint inflammation.

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