Robert D. Schreiber

Impaired response to interferon-alpha/beta and lethal viral disease in human STAT1 deficiency.

The receptors for interferon-α/β (IFN-α/β) and IFN-γ activate components of the Janus kinase–signal transducer and activator of transcription (JAK–STAT) signaling pathway, leading to the formation of at least two transcription factor complexes. STAT1 interacts with STAT2 and p48/IRF-9 to form the transcription factor IFN-stimulated gene factor 3 (ISGF3). STAT1 dimers form γ-activated factor (GAF). ISGF3 is induced mainly by IFN-α/β, and GAF by IFN-γ, although both factors can be activated by both types of IFN. Individuals with mutations in either chain of the IFN-γ receptor (IFN-γR) are susceptible to infection with mycobacteria. A heterozygous STAT1 mutation that impairs GAF but not ISGF3 activation has been found in other individuals with mycobacterial disease. No individuals with deleterious mutations in the IFN-α/β signaling pathway have been described. We report here two unrelated infants homozygous with respect to mutated STAT1 alleles. Neither IFN-α/β nor IFN-γ activated STAT1-containing transcription factors. Like individuals with IFN-γR deficiency, both infants suffered from mycobacterial disease, but unlike individuals with IFN-γR deficiency, both died of viral disease. Viral multiplication was not inhibited by recombinant IFN-α/β in cell lines from the two individuals. Inherited impairment of the STAT1-dependent response to human IFN-α/β thus results in susceptibility to viral disease.

The roles of IFNγ in protection against tumor development and cancer immunoediting

Interferon-gamma (IFN gamma) is a cytokine that plays physiologically important roles in promoting innate and adaptive immune responses. The absence of IFN gamma production or cellular responsiveness in humans and experimental animals significantly predisposes the host to microbial infection, a result that validates the physiologic importance of this cytokine in preventing infectious disease. Recently, an additional role for IFN gamma in preventing development of primary and transplanted tumors has been identified. Although there now appears to be a consensus that IFN gamma promotes host responses to tumors, the mechanisms by which this cytokine achieves its effects remain unclear. In this review, we briefly discuss key issues of the molecular cell biology of IFN gamma and its receptor that are most relevant to IFN gamma-dependent anti-tumor effects and then focus on the data implicating IFN gamma as a critical immune system component that regulates tumor development. Potential mechanisms underlying IFN gammas anti-tumor effects are discussed and a preliminary integrative model of IFN gammas actions on tumors is proposed. Finally, the capacity of IFN gamma and lymphocytes to not only provide protection against tumor development but also to sculpt the immunogenic phenotype of tumors that develop in an immunocompetent host is presented and introduced as a cancer immunoediting process.

Suppressor of cytokine signaling 1 regulates the immune response to infection by a unique inhibition of type I interferon activity

Suppressor of cytokine signaling 1 (SOCS1) is a critical regulator of cytokine signaling and immune responses. SOCS1-deficient mice develop severe inflammatory disease, but are very resistant to viral infections. Using neutralizing antibody to type I interferon (IFN-α and IFN-β) and mice deficient in interferon-γ or type I interferon receptor components (IFNAR1 or IFNAR2), we demonstrate here that SOCS1 deficiency amplified type I interferon antiviral and proinflammatory actions independently of interferon-γ. The mechanism of the suppression of type I interferon responses by SOCS1 was distinct from that of other cytokines. SOCS1 associated with and regulated IFNAR1- but not IFNAR2-specific signals, abrogating tyrosine phosphorylation of transcription factor STAT1 and reducing the duration of antiviral gene expression. Thus, SOCS1 is an important in vivo inhibitor of type I interferon signaling and contributes to balancing its beneficial antiviral versus detrimental proinflammatory effects on innate immunity.

Letters to the EditorA Causative Relationship between Mutant IFNgR1 Alleles and Impaired Cellular Response to IFNγ in a Compound Heterozygous Child

We thank Dr. Jane Peake for critical reading, Dr. Stephane Blanche for referral of the patient, Dr. Jean-Louis Gaillard for identification of mycobacterial species, and Drs. Cherif Beldjord and Erwin Schurr for DNA samples.J.-L.C. wishes to thank Dr. Francois Godeau for his friendly encouragement. This work was supported by grants from the Institut National de la Sante et de la Recherche Medicale and Association Francaise contre les Myopathies of the Institut Necker. F.A. is supported by the Fondation Marcel Merieux, E.J. by the Institut Lilly, S.L.-C. by the Centre International des Etudiants et Stagiaires, and J.-L.C. by the Fonds dEtudes et de Recherches des Hopitaux de Paris. This study was approved by the institutional review board, and informed consent was obtained from the family members.

A Novel c-Jun-dependent Signal Transduction Pathway Necessary for the Transcriptional Activation of Interferon γ Response Genes

The biological effects of interferon γ (IFNγ) are mediated by interferon-stimulated genes (ISGs), many of which are activated downstream of Janus kinase (JAK)/signal transducer and activator of transcription 1 (STAT1) signaling. Herein we have shown that IFNγ rapidly activated AP-1 DNA binding that required c-Jun but was independent of JAK1 and STAT1. IFNγ-induced c-Jun phosphorylation and AP-1 DNA binding required the MEK1/2 and ERK1/2 signaling pathways, whereas the JNK1/2 and p38 mitogen-activated protein kinase pathways were dispensable. The induction of several ISGs, including ifi-205 and iNOS, was impaired in IFNγ-treated c-Jun–/– cells, but others, such as IP-10 and SOCS3, were unaffected, and chromatin immunoprecipitation demonstrated that c-Jun binds to the iNOS promoter following treatment with IFNγ. Thus, IFNγ induced JAK1- and STAT1-independent activation of the ERK mitogen-activated protein kinase pathway, phosphorylation of c-Jun, and activation of AP-1 DNA binding, which are important for the induction of a subset of ISGs. This represents a novel signal transduction pathway induced by IFNγ that proceeds in parallel with conventional JAK/STAT signaling to activate ISGs.

Stat-1 Is Not Essential for Inhibition of B Lymphopoiesis by Type I IFNs

Type I IFNs, IFN-α, -β, and -ω, are cytokine family members with multiple immune response roles, including the promotion of cell growth and differentiation. Conversely, the type I IFNs are potent inhibitors of IL-7-dependent growth of early B lineage progenitors, effectively aborting further B lineage differentiation at the pro-B cell stage. Type I IFNs α and β function via receptor-mediated activation of a Jak/Stat signaling pathway in which Stat-1 is functionally important, because many IFN-induced responses are abrogated in Stat-1-deficient mice. To the contrary, we show here that the inhibition of IL-7-dependent B lymphopoiesis by IFN-αβ is unaffected in Stat-1-deficient mice. The present data indicate that the type I IFNs can activate an alternative signaling pathway in which neither Stat-1 nor phosphatidylinositol 3′-kinase are essential components.

Lymphokine regulation of macrophage effector activities.

Our concept of the regulation of macrophage activation is ever expanding and contracting. In regard to the number of LK that regulate macrophages killing activities, we have entered a new phase. In the beginning there was one macrophage activation factor, MIF; then there were many macrophage activation factors, most uncharacterized and bearing a variety of names. Then came IFN, a genetically cloned single reagent that induced destruction of virtually every target assessed; all activities of macrophages were assumed to be regulated by IFN. Once again, however, the LK universe is expanding: the number of single, cloned reagents that induce macrophage killing activities is amazing. With just two targets, a fibrosarcoma cell and an intracellular amastigote of L. major, we can identify 5 different macrophage activation factors, four of which are cloned and sequenced. As more recombinant reagents become available, the story of macrophage activation is likely to become even more complex. It is fascinating not only that certain of the LK are capable of inducing single effector reactions in the absence of effects on other effector activities, but also that at least one effector reaction requires the cooperation of several molecularly distinct LK. The complexity of LK activation factors that regulate a single effector reaction in vitro is compounded by the complexity in effector cell populations. For example, inflammatory macrophages exposed to LK kill the fibrosarcoma tumor target 5 to 10-fold better than an equal number of resident peritoneal macrophages. In contrast, LK treated resident macrophages eliminate intracellular amastigotes of leishmania far more efficiently than inflammatory cells. Thus, changes in cell populations dramatically affect the capacity to demonstrate a single effector reaction. Further, simple changes in assay conditions also determine whether an effector reaction can be observed in vitro. And superimposed upon all these layers of complexity is the target itself. The mechanisms a macrophages uses to block the replication of a virus may be totally ineffective in the destruction of a multicellular helminth, such as Schistosoma mansoni. And there is no reason to suspect that the extracellular destruction of a tumor target occurs by the same means that the macrophage uses to kill an intracytoplasmic bacterium, such as a rickettsia.(ABSTRACT TRUNCATED AT 400 WORDS)