Role of Suppressor of cytokine signaling 2 during the development and resolution of an experimental arthritis.

Rheumatoid arthritis(RA) is a debilitating chronic inflammatory disease. Suppressors of Cytokine Signaling(SOCS) proteins regulate homeostasis and pathogenesis in several diseases. The intersection between RA pathophysiology and SOCS2 is unclear. Herein, we investigated the roles of SOCS2 during the development of an experimental antigen-induced arthritis(AIA). In wild type mice, joint SOCS2 expression was reduced during AIA development. At the peak of inflammation, SOCS2-/- mice presented with reduced numbers of infiltrated cells in their joints. At the late phase of AIA, however, exhibited increased adhesion/infiltration of neutrophils, macrophages, CD4+-T cells, CD4+CD8+-T cells, and CD4-CD8--T cells associated with elevated IL-17 and IFN-γ levels, joint damage, proteoglycan loss, and nociception. SOCS2 deficiency resulted in lower numbers of apoptotic neutrophils and reduced efferocytosis. The present study demonstrated the vital role of SOCS2 during the development and resolution of an experimental RA model. Hence, this protein may be a novel therapeutic target for this disorder.

CISH constrains the tuft-ILC2 circuit to set epithelial and immune tone.

Innate lymphoid cells (ILCs) are tissue-resident effectors poised to activate rapidly in response to local signals such as cytokines. To preserve homeostasis, ILCs must employ multiple pathways, including tonic suppressive mechanisms, to regulate their primed state and prevent inappropriate activation and immunopathology. Such mechanisms remain incompletely characterized. Here we show that cytokine-inducible SH2-containing protein (CISH), a suppressor of cytokine signaling (SOCS) family member, is highly and constitutively expressed in type 2 innate lymphoid cells (ILC2s). Mice that lack CISH either globally or conditionally in ILC2s show increased ILC2 expansion and activation, in association with reduced expression of genes inhibiting cell-cycle progression. Augmented proliferation and activation of CISH-deficient ILC2s increases basal and inflammation-induced numbers of intestinal tuft cells and accelerates clearance of the model helminth, Nippostrongylus brasiliensis, but compromises innate control of Salmonella typhimurium. Thus, CISH constrains ILC2 activity both tonically and after perturbation, and contributes to the regulation of immunity in mucosal tissue.

Heart defects and embryonic lethality in Asb2 knock out mice correlate with placental defects.

Asb2, ankyrin repeat, and SOCS box protein 2 form an E3 ubiquitin ligase complex. Asb2 ubiquitin ligase activity drives the degradation of filamins, which have essential functions in humans. The placenta is a temporary organ that forms during pregnancy, and normal placentation is important for survival and growth of the fetus. Recent studies have shown that approximately 25-30% of knockout (KO) mice have non-viable offspring, and 68% of knockout lines exhibit placental dysmorphologies. There are very few studies on Asb2, with insufficient research on its role in placental development. Therefore, we generated Asb2 knockout mice and undertook to investigate Asb2 expression during organogenesis, and to identify its role in early embryonic and placental development. The external morphology of KO embryos revealed abnormal phenotypes including growth retardation, pericardial effusion, pale color, and especially heart beat defect from E 9.5. Furthermore, Asb2 expression was observed in the heart from E 9.5, indicating that it is specifically expressed during early heart formation, resulting in embryonic lethality. Histological analysis of E 10.5 KO heart showed malformations such as failure of chamber formation, reduction in trabeculated myocardium length, absence of mesenchymal cells, and destruction of myocardium wall. Moreover, the histological results of Asb2-deficient placenta showed abnormal phenotypes including small labyrinth and reduced vascular complexity, indicating that failure to establish mature circulatory pattern affects the embryonic development and results in early mortality. Collectively, our results demonstrate that Asb2 knockout mice have placental defects, that subsequently result in failure to form a normal cardiac septum, and thereby result in embryo mortality in utero at around E 9.5.

Inhibition of SOCS6 confers radioresistance in esophageal squamous cell carcinoma.

Esophageal cancer is one of the most common cancer of the digestive system and radiotherapy is widely applied in advanced esophageal cancer treatment, however radioresistance (RR) is one of the major reasons for radiotherapy failure. There is limited knowledge on the mechanisms that cause RR, here we identify suppressors of cytokine signaling 6 (SOCS6) is a negative regulator of radioresistance in ESCC cells. SOCS6 deficiency in ESCC cells conferred radioresistance in vitro and in vivo by increasing radiation-induced G2/M arrest, DNA damage repair and inhibiting radiation-induced apoptosis. Moreover, the transcriptome sequencing analysis demonstrates that the transcription of SOCS6 was partially p53-dependent. Importantly we found that highly correlated SOCS6 and P53 express lower in RR esophageal cancer tissues compare with radiosensitive ones. Collectedly our study uncovers that SOCS6, as a downstream effector of p53, is a key regulator involved in the radioresistance of ESCC.

SOCS2 Silencing Improves Somatic Growth without Worsening Kidney Function in CKD.

BACKGROUND: Growth hormone (GH) resistance in CKD is partly due to increased expression of SOCS2, a GH signaling negative regulator. In SOCS2 absence, body growth is exaggerated. However, GH overexpression in mice causes glomerulosclerosis. Accordingly, we tested whether lack of SOCS2 improves body growth, but accelerates kidney damage in CKD. METHODS: Eight-week-old mutant SOCS2-deficient high growth (HG) and normal wild-type mice (N) underwent 5/6 nephrectomy (CKD) or sham operation (C) and were sacrificed after 12 weeks, generating 4 groups: C-N, C-HG, CKD-N, CKD-HG. RESULTS: Somatic growth, inhibited in CKD-N, increased significantly in CKD-HG. Liver p-STAT5, a key intracellular signal of GH receptor (GHR) activation, was decreased in CKD-N but not in CKD-HG. Serum Cr as well as histopathological scores of renal fibrosis were similar in both CKD groups. Kidney fibrogenic (TGF-ß and collagen type IV mRNA) and inflammatory precursors (IL6, STAT3, and SOCS3 mRNA) were similarly increased in C-HG, CKD-HG, and CKD-N versus C-N. Renal GHR mRNA was decreased in C-HG, CKD-HG, and CKD-N versus C-N. Kidney p-STAT5 was decreased in CKD-N but not elevated in CKD-HG. CONCLUSIONS: CKD-related growth retardation is overcome by SOCS2 silencing, in association with increased hepatic STAT5 phosphorylation. Renal insufficiency is not worsened by SOCS2 absence, as kidney GHR and STAT5 are not upregulated. This may be due to elevated kidney proinflammatory cytokines and their mediators, phospho-STAT3 and SOCS3, which may counteract for the absence in SOCS2 and explain the renal safety of prolonged GH therapy in CKD.

RBX2 maintains final retinal cell position in a DAB1-dependent and -independent fashion.

The laminated structure of the retina is fundamental for the organization of the synaptic circuitry that translates light input into patterns of action potentials. However, the molecular mechanisms underlying cell migration and layering of the retina are poorly understood. Here, we show that RBX2, a core component of the E3 ubiquitin ligase CRL5, is essential for retinal layering and function. RBX2 regulates the final cell position of rod bipolar cells, cone photoreceptors and Muller glia. Our data indicate that sustained RELN/DAB1 signaling, triggered by depletion of RBX2 or SOCS7 - a CRL5 substrate adaptor known to recruit DAB1 - causes rod bipolar cell misposition. Moreover, whereas SOCS7 also controls Muller glia cell lamination, it is not responsible for cone photoreceptor positioning, suggesting that RBX2, most likely through CRL5 activity, controls other signaling pathways required for proper cone localization. Furthermore, RBX2 depletion reduces the number of ribbon synapses and disrupts cone photoreceptor function. Together, these results uncover RBX2 as a crucial molecular regulator of retina morphogenesis and cone photoreceptor function.

Suppressor of cytokine signaling 2 (Socs2) deletion protects bone health of mice with DSS-induced inflammatory bowel disease.

Individuals with inflammatory bowel disease (IBD) often present with poor bone health. The development of targeted therapies for this bone loss requires a fuller understanding of the underlying cellular mechanisms. Although bone loss in IBD is multifactorial, the altered sensitivity and secretion of growth hormone (GH) and insulin-like growth factor-1 (IGF-1) in IBD is understood to be a critical contributing mechanism. The expression of suppressor of cytokine signaling 2 (SOCS2), a well-established negative regulator of GH signaling, is stimulated by proinflammatory cytokines. Therefore, it is likely that SOCS2 expression represents a critical mediator through which proinflammatory cytokines inhibit GH/IGF-1 signaling and decrease bone quality in IBD. Using the dextran sodium sulfate (DSS) model of colitis, we reveal that endogenously elevated GH function in the Socs2-/- mouse protects the skeleton from osteopenia. Micro-computed tomography assessment of DSS-treated wild-type (WT) mice revealed a worsened trabecular architecture compared to control mice. Specifically, DSS-treated WT mice had significantly decreased bone volume, trabecular thickness and trabecular number, and a resulting increase in trabecular separation. In comparison, the trabecular bone of Socs2-deficient mice was partially protected from the adverse effects of DSS. The reduction in a number of parameters, including bone volume, was less, and no changes were observed in trabecular thickness or separation. This protected phenotype was unlikely to be a consequence of improved mucosal health in the DSS-treated Socs2-/- mice but rather a result of unregulated GH signaling directly on bone. These studies indicate that the absence of SOCS2 is protective against bone loss typical of IBD. This study also provides an improved understanding of the relative effects of GH/IGF-1 signaling on bone health in experimental colitis, information that is essential before these drugs are explored as bone protective agents in children and adults with IBD.

CISH controls bacterial burden early after infection with Mycobacterium tuberculosis in mice.

CISH gene has been associated with increased susceptibility to human tuberculosis. We found that cish-/- mice had higher M. tuberculosis load in spleens and lungs up to 2.5 weeks after infection but not later compared to controls. Cish mRNA levels were increased in lungs at early and late time points after M. tuberculosis infection. In relation, the titers of inos and tnf mRNA in lungs were reduced early after infection of cish-/- mice. The transfer of cish-/- and control T cells conferred rag1-/- mice similar protection to infection with M. tuberculosis. Macrophages showed increased cish mRNA levels after M. tuberculosis infection in vitro. However, mycobacterial uptake and growth in cish-/- and control macrophages was similar. Thus, we here show that CISH mediates control of M. tuberculosis in mice early after infection via regulation of innate immune mechanisms.

Suppressor of Cytokine Signaling 2 Negatively Regulates NK Cell Differentiation by Inhibiting JAK2 Activity.

Suppressor of cytokine signaling (SOCS) proteins are negative regulators of cytokine responses. Although recent reports have shown regulatory roles for SOCS proteins in innate and adaptive immunity, their roles in natural killer (NK) cell development are largely unknown. Here, we show that SOCS2 is involved in NK cell development. SOCS2-/- mice showed a high frequency of NK cells in the bone marrow and spleen. Knockdown of SOCS2 was associated with enhanced differentiation of NK cells in vitro, and the transplantation of hematopoietic stem cells (HSCs) into congenic mice resulted in enhanced differentiation in SOCS2-/- HSCs. We found that SOCS2 could inhibit Janus kinase 2 (JAK2) activity and JAK2-STAT5 signaling pathways via direct interaction with JAK2. Furthermore, SOCS2-/- mice showed a reduction in lung metastases and an increase in survival following melanoma challenge. Overall, our findings suggest that SOCS2 negatively regulates the development of NK cells by inhibiting JAK2 activity via direct interaction.

The ubiquitin ligase Cullin5SOCS2 regulates NDR1/STK38 stability and NF-κB transactivation.

SOCS2 is a pleiotropic E3 ligase. Its deficiency is associated with gigantism and organismal lethality upon inflammatory challenge. However, mechanistic understanding of SOCS2 function is dismal due to our unawareness of its protein substrates. We performed a mass spectrometry based proteomic profiling upon SOCS2 depletion and yield quantitative data for ~4200 proteins. Through this screen we identify a novel target of SOCS2, the serine-threonine kinase NDR1. Over-expression of SOCS2 accelerates turnover, while its knockdown stabilizes, endogenous NDR1 protein. SOCS2 interacts with NDR1 and promotes its degradation through K48-linked ubiquitination. Functionally, over-expression of SOCS2 antagonizes NDR1-induced TNFα-stimulated NF-κB activity. Conversely, depletion of NDR1 rescues the effect of SOCS2-deficiency on TNFα-induced NF-κB transactivation. Using a SOCS2-/- mice model of colitis we show that SOCS2-deficiency is pro-inflammatory and negatively correlates with NDR1 and nuclear p65 levels. Lastly, we provide evidence to suggest that NDR1 acts as an oncogene in prostate cancer. To the best of our knowledge, this is the first report of an identified E3 ligase for NDR1. These results might explain how SOCS2-deficiency leads to hyper-activation of NF-κB and downstream pathological implications and posits that SOCS2 induced degradation of NDR1 may act as a switch in restricting TNFα-NF-κB pathway.

Suppressor of cytokine signaling (SOCS)5 ameliorates influenza infection via inhibition of EGFR signaling.

Influenza virus infections have a significant impact on global human health. Individuals with suppressed immunity, or suffering from chronic inflammatory conditions such as COPD, are particularly susceptible to influenza. Here we show that suppressor of cytokine signaling (SOCS) five has a pivotal role in restricting influenza A virus in the airway epithelium, through the regulation of epidermal growth factor receptor (EGFR). Socs5-deficient mice exhibit heightened disease severity, with increased viral titres and weight loss. Socs5 levels were differentially regulated in response to distinct influenza viruses (H1N1, H3N2, H5N1 and H11N9) and were reduced in primary epithelial cells from COPD patients, again correlating with increased susceptibility to influenza. Importantly, restoration of SOCS5 levels restricted influenza virus infection, suggesting that manipulating SOCS5 expression and/or SOCS5 targets might be a novel therapeutic approach to influenza.

Cortical Layer Inversion and Deregulation of Reelin Signaling in the Absence of SOCS6 and SOCS7.

Mutations of the reelin gene cause severe defects in cerebral cortex development and profound intellectual impairment. While many aspects of the reelin signaling pathway have been identified, the molecular and ultimate cellular consequences of reelin signaling remain unknown. Specifically, it is unclear if termination of reelin signaling is as important for normal cortical neuron migration as activation of reelin signaling. Using mice that are single or double deficient, we discovered that combined loss of the suppressors of cytokine signaling, SOCS6 and SOCS7, recapitulated the cortical layer inversion seen in mice lacking reelin and led to a dramatic increase in the reelin signaling molecule disabled (DAB1) in the cortex. The SRC homology domains of SOCS6 and SOCS7 bound DAB1 ex vivo. Mutation of DAB1 greatly diminished binding and protected from degradation by SOCS6. Phosphorylated DAB1 was elevated in cortical neurons in the absence of SOCS6 and SOCS7. Thus, constitutive activation of reelin signaling was observed to be equally detrimental as lack of activation. We hypothesize that, by terminating reelin signaling, SOCS6 and SOCS7 may allow new cycles of reelin signaling to occur and that these may be essential for cortical neuron migration.

Nicotinamide benefits both mothers and pups in two contrasting mouse models of preeclampsia.

Preeclampsia (PE) complicates ∼5% of human pregnancies and is one of the leading causes of pregnancy-related maternal deaths. The only definitive treatment, induced delivery, invariably results in prematurity, and in severe early-onset cases may lead to fetal death. Many currently available antihypertensive drugs are teratogenic and therefore precluded from use. Nonteratogenic antihypertensives help control maternal blood pressure in PE, but results in preventing preterm delivery and correcting fetal growth restriction (FGR) that also occurs in PE have been disappointing. Here we show that dietary nicotinamide, a nonteratogenic amide of vitamin B3, improves the maternal condition, prolongs pregnancies, and prevents FGR in two contrasting mouse models of PE. The first is caused by endotheliosis due to excess levels in the mothers of a soluble form of the receptor for vascular endothelial growth factor (VEGF), which binds to and inactivates VEGF. The second is caused by genetic absence of Ankiryn-repeat-and-SOCS-box-containing-protein 4, a factor that contributes to the differentiation of trophoblast stem cells into the giant trophoblast cells necessary for embryo implantation in mice; its absence leads to impaired placental development. In both models, fetal production of ATP is impaired and FGR is observed. We show here that nicotinamide decreases blood pressure and endotheliosis in the mothers, probably by inhibiting ADP ribosyl cyclase (ADPRC), and prevents FGR, probably by normalizing fetal ATP synthesis via the nucleotide salvage pathway. Because nicotinamide benefits both dams and pups, it merits evaluation for preventing or treating PE in humans.

Suppressor of cytokine signaling 2 (SOCS2) contributes to encephalitis in a model of Herpes infection in mice.

The most severe manifestation of Herpes Simplex Type 1 virus (HSV-1) infection is encephalitis characterized by arousal impairment and seizures that can evolve to coma and death. Previous studies reported the involvement of suppressor of cytokine signaling (SOCS) proteins, specifically SOCS1 and SOCS3, in HSV-1 infection, suggesting that other members of this family could be involved in the immune response against HSV-1. No previous study has reported the role of SOCS2 in HSV-1 infection. In the current study, C57BL/6 wild-type mice (WT) and mice deficient in SOCS2 gene (SOCS2-/-) were subjected to intracranial inoculation with 102 plaque forming units (PFU) of HSV-1. Survival curve, neuroinflammatory parameters and neuropathology were evaluated. Infected SOCS2-/- mice had increased survival in comparison with infected WT animals. This better outcome was associated with reduced leukocyte infiltration, concentration of cytokines, and structural changes in the brain. SOCS2 seems to play a detrimental role in HSV-1 encephalitis. Moreover, the control of neuroinflammatory response in HSV-1 infection was of paramount importance to clinical outcome.

Role of the suppressor of cytokine signaling 2 (SOCS2) during meningoencephalitis caused by Bovine herpesvirus 5 (BoHV-5).

The role of suppressors of cytokine signaling (SOCS) in meningoencephalitis caused by Bovine herpesvirus 5 (BoHV-5) was evaluated by intracranial infection in C57BL/6 wild-type mice (WT) and SOCS2 deficient mice (SOCS2(-/-)). Both infected groups presented weight loss, ruffled fur and hunched posture. Additionally, infected SOCS2(-/-) mice showed swollen chamfer and progressive depression. Infected WT animals developed mild meningitis, characterized by infiltration of mononuclear cells. Moreover, viral DNA was detected in liver and lung from infected WT group. This group also showed elevated brain levels of IFN-γ, IL-10, CXCL1 and CCL5, when compared with non-infected WT animals. Brain inflammation was exacerbated in infected SOCS2(-/-) mice with widespread distribution of the virus and increased brain levels of TNF-α, IFN-γ, IL-10, IL-12, CXCL1 and CCL5, when compared with WT infected mice. Moreover, infected SOCS2 deficient mice exhibited reduced brain mRNA expression of IFNα and IFNß and increased expression of mRNA of SOCS1, compared with infected WT mice. Taken together, our study provides an insight into the role of SOCS2 in modulating the immune response to BoHV-5 infection.

Suppressor of cytokine signaling 2 modulates the immune response profile and development of experimental cerebral malaria.

Plasmodium falciparum infection results in severe malaria in humans, affecting various organs, including the liver, spleen and brain, and resulting in high morbidity and mortality. The Plasmodium berghei ANKA (PbA) infection in mice closely recapitulates many aspects of human cerebral malaria (CM); thus, this model has been used to investigate the pathogenesis of CM. Suppressor of cytokine signaling 2 (SOCS2), an intracellular protein induced by cytokines and hormones, modulates the immune response, neural development, neurogenesis and neurotrophic pathways. However, the role of SOCS2 during CM remains unknown. SOCS2 knockout (SOCS2(-/-)) mice infected with PbA show an initial resistance to infection with reduced parasitemia and production of TNF, TGF-ß, IL-12 and IL-17 in the brain. Interestingly, in the late phase of infection, SOCS2(-/-) mice display increased parasitemia and reduced Treg cell infiltration, associated with enhanced levels of Th1 and Th17 cells and related cytokines IL-17, IL-6, and TGF-ß in the brain. A significant reduction in protective neurotrophic factors, such as glial cell line-derived neurotrophic factor (GDNF) and brain-derived neurotrophic factor (BDNF), was also observed. Moreover, the molecular alterations in the brain of infected SOCS2(-/-) mice were associated with anxiety-related behaviors and cognition impairment. Mechanistically, these results revealed enhanced nitric oxide (NO) production in PbA-infected SOCS2(-/-) mice, and the inhibition of NO synthesis through l-NAME led to a marked decrease in survival, the disruption of parasitemia control and more pronounced anxiety-like behavior. Treatment with l-NAME also shifted the levels of Th1, Th7 and Treg cells in the brains of infected SOCS2(-/-) mice to the background levels observed in infected WT, with remarkable exception of increased CD8(+)IFN(+) T cells and inflammatory monocytes. These results indicate that SOCS2 plays a dual role during PbA infection, being detrimental in the control of the parasite replication but crucial in the regulation of the immune response and production of neurotrophic factors. Here, we provided strong evidence of a critical relationship between SOCS2 and NO in the orchestration of the immune response and development of CM during PbA infection.

Cish actively silences TCR signaling in CD8+ T cells to maintain tumor tolerance.

Improving the functional avidity of effector T cells is critical in overcoming inhibitory factors within the tumor microenvironment and eliciting tumor regression. We have found that Cish, a member of the suppressor of cytokine signaling (SOCS) family, is induced by TCR stimulation in CD8(+) T cells and inhibits their functional avidity against tumors. Genetic deletion of Cish in CD8(+) T cells enhances their expansion, functional avidity, and cytokine polyfunctionality, resulting in pronounced and durable regression of established tumors. Although Cish is commonly thought to block STAT5 activation, we found that the primary molecular basis of Cish suppression is through inhibition of TCR signaling. Cish physically interacts with the TCR intermediate PLC-γ1, targeting it for proteasomal degradation after TCR stimulation. These findings establish a novel targetable interaction that regulates the functional avidity of tumor-specific CD8(+) T cells and can be manipulated to improve adoptive cancer immunotherapy.

Suppression of microRNA-155 attenuates neuropathic pain by regulating SOCS1 signalling pathway.

Chronic neuropathic pain is an unfavourable pathological pain characterised by allodynia and hyperalgesia which has brought considerable trouble to people's physical and mental health, but effective therapeutics are still lacking. MicroRNAs (miRNAs) have been widely studied in the development of neuropathic pain and neuronal inflammation. Among various miRNAs, miR-155 has been widely studied. It is intensively involved in regulating inflammation-associated diseases. However, the role of miR-155 in regulating neuropathic pain development is poorly understood. In the present study, we aimed to investigate whether miR-155 is associated with neuropathic pain and delineate the underlying mechanism. Using a neuropathic pain model of chronic constriction injury (CCI), miR-155 expression levels were markedly increased in the spinal cord. Inhibition of miR-155 significantly attenuated mechanical allodynia, thermal hyperalgesia and proinflammatory cytokine expression. We also demonstrated that miR-155 directly bound with the 3'-untranslated region of the suppressor of cytokine signalling 1 (SOCS1). The expression of SOCS1 significantly decreased in the CCI rat model, but this effect could be reversed by miR-155 inhibition. Furthermore, knockdown of SOCS1 abrogated the inhibitory effects of miR-155 inhibition on neuropathic development and neuronal inflammation. Finally, we demonstrated that inhibition of miR-155 resulted in the suppression of nuclear factor-κB and p38 mitogen-activated protein kinase activation by mediating SOCS1. Our data demonstrate the critical role of miR-155 in regulating neuropathic pain through SOCS1, and suggest that miR-155 may be an important and potential target in preventing neuropathic pain development.

Expression of suppressor of cytokine signaling 1 (SOCS1) impairs viral clearance and exacerbates lung injury during influenza infection.

Suppressor of cytokine signaling (SOCS) proteins are inducible feedback inhibitors of cytokine signaling. SOCS1-/- mice die within three weeks postnatally due to IFN-γ-induced hyperinflammation. Since it is well established that IFN-γ is dispensable for protection against influenza infection, we generated SOCS1-/-IFN-γ-/- mice to determine whether SOCS1 regulates antiviral immunity in vivo. Here we show that SOCS1-/-IFN-γ-/- mice exhibited significantly enhanced resistance to influenza infection, as evidenced by improved viral clearance, attenuated acute lung damage, and consequently increased survival rates compared to either IFN-γ-/- or WT animals. Enhanced viral clearance in SOCS1-/-IFN-γ-/- mice coincided with a rapid onset of adaptive immune responses during acute infection, while their reduced lung injury was associated with decreased inflammatory cell infiltration at the resolution phase of infection. We further determined the contribution of SOCS1-deficient T cells to antiviral immunity. Anti-CD4 antibody treatment of SOCS1-/-IFN-γ-/- mice had no significant effect on their enhanced resistance to influenza infection, while CD8+ splenocytes from SOCS1-/-IFN-γ-/- mice were sufficient to rescue RAG1-/- animals from an otherwise lethal infection. Surprisingly, despite their markedly reduced viral burdens, RAG1-/- mice reconstituted with SOCS1-/-IFN-γ-/- adaptive immune cells failed to ameliorate influenza-induced lung injury. In conclusion, in the absence of IFN-γ, the cytoplasmic protein SOCS1 not only inhibits adaptive antiviral immune responses but also exacerbates inflammatory lung damage. Importantly, these detrimental effects of SOCS1 are conveyed through discrete cell populations. Specifically, while SOCS1 expression in adaptive immune cells is sufficient to inhibit antiviral immunity, SOCS1 in innate/stromal cells is responsible for aggravated lung injury.

Signal transducer and activator of transcription 1 (STAT1) acts like an oncogene in malignant pleural mesothelioma.

Malignant pleural mesothelioma (MPM) is the most common primary tumor of the pleura. Its incidence is increasing in Europe and the prognosis remains poor. We compared epithelioid MPM in short and long survivors, and identified signal transducer and activator of transcription 1 (STAT1) as probably being responsible for antiapoptotic signaling and chemoresistance. Six mesothelioma cell lines were evaluated by Western Blot. We also analyzed 16 epithelioid MPM tissue samples for the phosphorylation status of STAT1 and the expression of its negative regulator, the suppressor of cytokine signaling 1 (SOCS1). Formalin-fixed and paraffin-embedded tissue specimens were evaluated by protein-lysate microarray and immunohistochemistry. We found STAT1 to be highly expressed and STAT3 downregulated in MPM cell lines. The expression of STAT1 phosphorylated on tyrosine 701 (Y701) was increased by interferon-gamma (IFN-γ) treatment, whereas SOCS1 was not expressed. The expression of STAT1 phosphorylated on serine 727 (S727) was not detected in mesothelioma cell lines and was not stimulated by IFN-γ. STAT1 was phosphorylated on tyrosine 701 and serine 727 in MPM tissue samples. The expression of pSTAT1-Y701 was increased compared to pSTAT1-S727. SOCS1 was again not detectable. STAT1 is upregulated in MPM, and its action may be prolonged by a loss of the negative regulator SOCS1. STAT1 might, therefore, be a target for therapeutic intervention, with the intention to restore apoptotic mechanisms and sensitivity to chemotherapy. However, other regulatory mechanisms need to be investigated to clarify if lack of expression of SOCS1 is the only reason for sustained STAT1 expression in MPM.