Cytokines and growth factors regulate multiple aspects of cell growth through their interactions with specific receptors. These receptors initiate signals directed at both the cytoplasmic and the nuclear compartments. Many of the nuclear signals culminate in the induction of new genes. Characterization of the ability of IFN-alpha to rapidly induce new genes has led to the identification of a new signaling paradigm, the JAK-STAT (Signal Transducers and Activators of Transcription) pathway. In the IFN-alpha pathway, two receptor associated tyrosine kinases from the JAK family, Jak1 and Tyk2, mediate the activation of two latent cytoplasmic transcription factors, Stat1 and Stat2. More recent studies have not only determined that this pathway is used extensively, but have led to the identification of additional components (e.g., Jak2, Jak3, Stat3, Stat4, Stat5, and Stat6). This review will examine how these components mediate the transduction of signal directly from receptor to nucleus.

50 years ago Isaacs and Lindenmann (1) first described interferons (IFNs) 2 as founding members of the cytokine family. Over the next 25 years, these and several other four-helix bundle cytokines were characterized. The subsequent 25 years witnessed an exponential growth in number of four-helix bundle cytokines and their corresponding receptors.The early availability of recombinant IFNs afforded an opportunity to investigate how cytokines induce gene expression, culminating in the identification of the JAK-STAT signaling paradigm (see Fig. 1). Subsequent studies identified 7 STATs and 4 JAKs, providing important insight into how the ϳ50 members of the four-helix bundle cytokine family transduce their potent biological responses. This review will briefly summarize this signaling paradigm (reviewed in Refs. 2-5) and then focus on STAT-dependent transcription.

The early colocalization of T cells and the potent immunostimulatory cytokine IFN-␥ to atherosclerotic lesions suggest that the immune system contributes to atherogenesis. Since mice with a targeted disruption of the apoE gene (apoE 0 mice) develop profound atherosclerosis, we examined the role of IFN-␥ in this process. First, the presence of CD4 ϩ and CD8 ϩ cells, which secrete lesional IFN-␥ , was documented in apoE 0 atheromata. Then, the apoE 0 mice were crossed with IFN-␥ receptor (IFN ␥ R) 0 mice to generate apoE 0/IFN ␥ R 0 mice. Compared to the apoE 0 mice, the compound knock-out mice exhibited a substantial reduction in atherosclerotic lesion size, a 60% reduction in lesion lipid accumulation, a decrease in lesion cellularity, but a marked increase in lesion collagen content. Evaluation of the plasma lipoproteins showed that the compound knockout mice had a marked increase in potentially atheroprotective phospholipid/apoA-IV rich particles as well. This correlated with an induction of hepatic apoA-IV transcripts. These observations suggest that IFN-␥ promotes and modifies atherosclerosis through both local effects in the arterial wall as well as a systemic effect on plasma lipoproteins. Therefore, therapeutic inhibition of IFN-␥ signaling may lead to the formation of more lipid-poor and stable atheromata. ( J. Clin. Invest. 1997. 99:2752-2761.)

Type I IFNs induce gene expression through Stat1 and Stat2, which can in turn associate either to form Stat1 homodimers or the transcription factor ISGF-3. Stat1 homodimers also transduce signals for IFN-gamma. To explore the unique properties of Stat2 and ISGF-3 in type I IFN signaling, its gene was targeted for deletion. Stat2 null mice exhibit a number of defects in immune response. This includes an increased susceptibility to viral infection and the loss of a type I IFN autocrine/ paracrine loop, which in turn regulates several aspects of immune response. Intriguingly, Stat2-deficient fibroblasts exhibit a more significant defect in their response to type I IFNs than macrophages, highlighting tissue-specific differences in the response to this family of ligands.

CUTE EXACERBATIONS OF chronic obstructive pulmonary disease (COPD) are a risk factor for disease deterioration, 1 and patients with frequent exacerbations have increased mortality. 2 In the general practitioner-based Swiss COPD cohort, approximately 23% to 25% of patients with COPD experienced exacerbations requiring pharmacological treatment within 1 year. 3,4 International guidelines and systematic reviews advocate systemic glucocorticoid therapy in the management of acute exacerbations of COPD (eg, 30-40 mg of oral prednisolone for 10-14 days). 5-7 Randomized clinical Author Affiliations are listed at the end of this article.