**2. JAKs**

JAKs are non-receptor tyrosine kinases that are pre-associated with the membrane-proximal site of cytokine receptors [16]. Four mammalian JAK isoforms, JAK1, JAK2 and JAK3 and TYK2 have been described to date mainly from the results of gene structural analysis [17]. All of the JAK isoforms share a common structure known as the JAK homology (JH) do‐

© 2013 Malemud; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

main. Leonard and O'Shea [18] identified a proline-rich conserved region in the cytokine re‐ ceptors, called Box1, that associated with JH7 whereas the catalytic phosphotyrosine kinase site, called YY was determined to correspond to the other JH domains (Figure 1).

ry and anti-inflammatory cytokine genes as well as other genes of significance in cancer and autoimmune diseases [23-28]. In addition, p-STAT proteins can regulate other signaling pathways necessary for lymphocyte development, as well as the aberrant survival of activat‐ ed dendritic cells, monocytes, lymphocytes and synoviocytes in disorders of the immune

Suppression of Pro-Inflammatory Cytokines via Targeting of STAT-Responsive Genes

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It is noteworthy that during normal homeostasis, activation of STAT proteins induced the expression of Suppressor of Cytokine Signaling (SOCS) and Cytokine-Inducible SH-2 (CIS) proteins and it has been concluded that this is the negative feedback loop that underlies one of the mechanisms responsible for inhibiting JAK-mediated signaling by cytokines [34-38]. Thus, results of recently published experiments with human endothelial cells are germane to this point since the data in this paper provided a direct connection between the silencing of

The extent to which negative regulation of JAK-mediated signaling by SOCS/CIS may be in‐ activated in autoimmune diseases is a focus of current studies. In that regard, recent advan‐ ces in unraveling the details of mechanism(s) governing negative regulation of cytokine signaling by SOCS/CIS proteins have shed additional light on the extent to which SOCS/CISmediated down-regulation of pro- and/or anti-inflammatory cytokine JAK/STAT signaling may be compromised in inflammatory arthritis [40]. However, the results of some recent studies with osteoarthritic human cartilage have not clarified this issue. For example, one study showed that the level of SOCS2 and CIS-1, but not SOCS1 and SOCS3, were reduced in femoral head cartilages from subjects with osteoarthritis [41], whilst the results of another study [42] indicated that SOCS3, but not SOCS1 expression, was elevated in chondrocytes obtained from osteoarthritic cartilage compared to chondrocytes from cartilage obtained

The status of the activity of certain other negative regulators such as protein tyrosine phos‐ phatases, including SHP-1,-2 [43] and CD45 [44] and the 'Protein Inhibitor of Activated STAT' (PIAS) proteins [16, 45, 46] are also not precisely known in autoimmune diseases. These proteins could very likely suppress the activity of phosphorylated JAKs and p-STAT proteins by dephosphorylation or by interacting with p-STAT proteins in normal cells.

It is also critical for gaining a further understanding of what alterations may occur in cyto‐ kine signaling in RA to recognize the fact that activation of JAK/STAT by any of the relevant cytokines can also activate other intracellular signaling pathways via the "cross-talk" mech‐ anism. Thus, "cross-talk" between JAK/STAT and other signaling pathways [16] can cause activation of the Stress-Activated Protein Kinase/Mitogen-Activated Protein Kinase (SAPK/ MAPK) pathway, the Phosphatidylinositol-3-Kinase/Akt/mammalian Target of Rapamycin (PI3K/Akt/mTOR) pathway [47], activation of signaling via Toll-like receptors [47, 48] and immunoreceptor tyrosine-based activation motifs (ITAMs) [49] as well as the NF-κB path‐ way [50]. These alternative signaling pathways which are all connected to inflammation have also been shown to significantly modulate many of the survival and/or apoptosis-sig‐ nals required to perpetuate abnormal proliferation and/or to cause the death of activated

However, these pathways may be compromised or markedly suppressed in arthritis.

dendritic cells, lymphocytes, macrophages, synoviocytes and chondrocytes.

STAT3 with STAT3-specific silencing RNA and the suppression of SOCS3 [39].

from patients who had femoral neck fracture.

system [29-33].

**Figure 1.** JH domains and phosphorylation sites of JAK3: Structural analysis combined with functional studies of JAK3 showed that the JH4-JH7 region contained band 4.1 also known as the Four-point-one, Ezrin, Radixin, Moesin (FERM) domain. Reprinted by permission from [16].

Additional structural analysis predicted that the JH2 domain was more than likely to be a pseudosubstrate domain [19]. In view of this latter finding the structural requirements for JAK activation was further clarified. Thus, the JH3-JH4 domain which shows a Src-homolo‐ gy-2-like structure had a shared homology with JH2. This finding indicated that the JH4-JH7 domains were, indeed, the critical regions required for regulating the interactions between the various JAK isoforms and other protein kinases. JH4-JH7 were also found to be essential for receptor binding, catalytic function, JAK autophosphorylation and even in some cases, inhibition of JAK activity.
