The interferon (IFN)‐induced double‐stranded RNA (dsRNA)‐activated Ser/Thr protein kinase (PKR) plays a role in the antiviral and antiproliferative effects of IFN. PKR phosphorylates initiation factor eIF2α, thereby inhibiting protein synthesis, and also activates the transcription factor, nuclear factor‐κB (NF‐κB), by phosphorylating the inhibitor of NF‐κB, IκB. Mice devoid of functional PKR (Pkr°/°) derived by targeted gene disruption exhibit a diminished response to IFN‐γ and poly(rI:rC) (pIC). In embryo fibroblasts derived from Pkr°/° mice, interferon regulatory factor 1 (IRF‐1) or guanylate binding protein (Gbp) promoter–reporter constructs were unresponsive to IFN‐γ or pIC but response could be restored by co‐transfection with PKR. The lack of responsiveness could be attributed to a diminished activation of IRF‐1 and/or NF‐κB in response to IFN‐γ or pIC. Thus, PKR acts as a signal transducer for IFN‐stimulated genes dependent on the transcription factors IRF‐1 and NF‐κB.

Intestinal fibrosis is a common complication of the inflammatory bowel diseases (IBDs). It becomes clinically apparent in >30% of patients with Crohn's disease (CD) and in about 5% with ulcerative colitis (UC). Fibrosis is a consequence of local chronic inflammation and is characterized by excessive extracellular matrix (ECM) protein deposition. ECM is produced by activated myofibroblasts, which are modulated by both, profibrotic and antifibrotic factors. Fibrosis depends on the balance between the production and degradation of ECM proteins. This equilibrium can be impacted by a complex and dynamic interaction between profibrotic and antifibrotic mediators. Despite the major therapeutic advances in the treatment of active inflammation in IBD over the past two decades, the incidence of intestinal strictures in CD has not significantly changed as the current anti-inflammatory therapies neither prevent nor reverse the established fibrosis and strictures. This implies that control of intestinal inflammation does not necessarily affect the associated fibrotic process. The conventional view that intestinal fibrosis is an inevitable and irreversible process in patients with IBD is also gradually changing in light of an improved understanding of the cellular and molecular mechanisms that underline the pathogenesis of fibrosis. Comprehension of the mechanisms of intestinal fibrosis is thus vital and may pave the way for the developments of antifibrotic agents and new therapeutic approaches in IBD.

Members of the suppressor of cytokine signaling (SOCS) family of signaling molecules regulate the activation of cytokine signaling. Experimental evidence indicates that SOCS expression is induced by cytokines and pro-inflammatory stimuli and is controlled at both the transcriptional and post-transcriptional levels. SOCS proteins are unstable and seem to be rapidly degraded by proteasomal pathways. However, the mechanisms by which SOCS protein levels are regulated remain unclear. Here, we show that TRIM8/GERP, a RING finger protein, interacts with SOCS-1 in vitro and in vivo. TRIM8/GERP, previously identified as a new member of the family of proteins containing a tripartite motif (TRIM), is a 551-amino acid RING finger protein conserved across species. TRIM8/GERP expression can be induced by interferon-␥ in epithelial and lymphoid cells. Coexpression of TRIM8/GERP with SOCS-1 decreases SOCS-1 protein stability and levels. Functionally, expression of TRIM8/GERP decreases the repression of interferon-␥ signaling mediated by SOCS-1. These data suggest that TRIM8/GERP may be a regulator of SOCS-1 function.Cytokines control many different cellular functions, including proliferation, differentiation, and gene expression (1, 2). Moreover, they participate in the pathophysiology of viral infections, play a central role in the development of the hematopoietic system, and have been implicated in the pathogenesis of autoimmune diseases (3, 4). The biological response of a cell to cytokines involves a complex network of signal transduction machinery. Signaling is initiated by the oligomerization of cognate cytokine receptors expressed on the surface of target cells (5), which triggers the activation of members of the JAK 1 family of protein-tyrosine kinases that constitutively associate with the cytokine receptor. Subsequently, JAKs can phosphorylate tyrosine residues present in the cytoplasmic regions of the receptors. These phosphorylated tyrosines then act as docking sites for signaling molecules, such as members of the STAT family of transcription factors (6).The intensity and duration of cytokine signaling seems to be regulated by several mechanisms. It is now known that at least three different classes of negative regulators contribute to cytokine inhibition: (i) the SH2-containing protein-tyrosine phosphatases 1 and 2 (7, 8), (ii) the protein inhibitors of activated STATs, and (iii) the suppressor of cytokine signaling (SOCS protein) (9 -13). Experimental data suggest that (i) SOCS genes are induced by cytokines; (ii) SOCS molecules can inhibit cytokine signaling by binding to downstream signaling molecules such as JAK kinases (14 -16); (iii) deregulated expression of SOCS proteins perturbs cytokine-related cellular proliferation and hematopoietic differentiation in murine tissues (17). Mice lacking SOCS-1 die shortly after birth from hepatic necrosis (18 -20). Data suggest that this lethality is due, at least in part, to hypersensitivity to IFN-␥ signaling. SOCS-2-deficient mice seem healthy after birth but develop a...

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