Long-term variations of aerosol optical depth and aerosol radiative forcing over Iran based on satellite and AERONET data.

In this study, three different sensors of satellites including the Moderate Resolution Imaging Spectroradiometer (MODIS), Multi-angle Imaging SpectroRadiometer (MISR), and Total Ozone Mapping Spectrometer (TOMS) were used to study spatial and temporal variations of aerosols over ten populated cities in Iran. Also, the Hybrid Single-Particle Lagrangian Integrated Trajectory (HYSPLIT) model was used for analyzing the origins of air masses and their trajectory in the area. An increasing trend in aerosol concentration was observed in the most studied cities in Iran during 1979-2016. The cities in the western part of Iran had the highest annual mean of aerosol concentration. The highest aerosol optical depth (AOD) value (0.76 ± 0.51) was recorded in May 2012 over Ahvaz, and the lowest value (0.035 ± 0.27) was recorded in December 2013 over Tabriz. After Ahvaz, the highest AOD value was found over Tehran (annual mean 0.11 ± 0.20). The results show that AOD increases with increasing industrial activities, but the increased frequency of aerosols due to land degradation and desertification is more powerful in Iran. The trajectory analysis by the HYSPLIT model showed that the air masses come from Egypt, Syria, and Lebanon and passed over the Iraq and then reached to Iran during summer. Aerosol radiative forcing (ARF) has been analyzed for Zanjan (Aerosol Robotic Network site) during 2010-2013. The ARF at surface and top of the atmosphere was found to be ranging from - 79 to - 10W m-2 (average - 33.45 W m-2) and from - 25 to 6 W m-2 (average - 12.80 W m-2), respectively.

Suppressor of cytokine signalling 1 (SOCS1) is a physiological regulator of the asthma response.

BACKGROUND: The molecular determinants of the severity and persistence of allergic asthma remain poorly understood. Suppressor of cytokine signalling 1 (SOCS1) is a negative regulator of IL-4-dependent pathways in vitro and might therefore control T-helper type 2 (Th2) immunity associated traits, such as IgE levels, mucin production, IL-5 and IL-13 induction, and eosinophilic mucosal inflammation, which are implicated in allergic asthma. OBJECTIVE: To investigate the role of SOCS1 in regulating Th2-associated disease traits in a murine sub-chronic aeroallergen-driven asthma model. METHODS: Following sensitization and challenge with ovalbumin (OVA), bronchoalveolar lavage and serum were collected from mice lacking the Socs1 gene on an IFN-gamma null background (Socs1(-/-)Ifngamma(-/-)). The composition of infiltrating cells in the lung, serum IgE and IgG1 levels and cytokine levels were analysed. RESULTS: Serum IgE levels and infiltrating eosinophils were considerably increased in the lungs of OVA-treated Socs1(-/-)Ifngamma(-/-) mice compared with Ifngamma(-/-) and C57BL/6 controls. Expression of the Th2 cytokines, IL-4, IL-5 and IL-13 was increased in CD4+ cells and lung tissue from OVA-treated Socs1(-/-)Ifngamma(-/-) mice. IgE, IL-5 levels and infiltrating eosinophils were also elevated in saline-treated Socs1(-/-)Ifngamma(-/-) mice, suggesting that in the absence of SOCS1, mice are already biased towards a Th2 response. It is at present unclear whether the elevated cytokine levels are sufficient to result in the exacerbated Th2 response to OVA challenge or whether enhanced intra-cellular signalling also contributes. Surprisingly, of the various IL-4/IL-13 responsive genes tested, only Arginase I appeared to be modestly up-regulated in the lungs of OVA-treated Socs1(-/-)Ifngamma(-/-) mice, suggesting that regulation by SOCS1 occurs primarily in haematopoietic cells and not in the airway epithelium. CONCLUSIONS: Together these results indicate that SOCS1 is an important regulator of the Th2 response.

Genetic deletion of murine SPRY domain-containing SOCS box protein 2 (SSB-2) results in very mild thrombocytopenia.

The SSB family is comprised of four highly homologous proteins containing a C-terminal SOCS box motif and a central SPRY domain. No function has yet been ascribed to any member of this family in mammalian species despite a clear role for other SOCS proteins in negative regulation of cytokine signaling. To investigate its physiological role, the murine Ssb-2 gene was deleted by homologous recombination. SSB-2-deficient mice were shown to have a reduced rate of platelet production, resulting in very mild thrombocytopenia (25% decrease in circulating platelets). Tissue histology and other hematological parameters were normal, as was the majority of serum biochemistry, with the exception that blood urea nitrogen (BUN) levels were decreased in mice lacking SSB-2. Quantitative analysis of SSB mRNA levels indicated that SSB-1, -2, and -3 were ubiquitously expressed; however, SSB-4 was only expressed at very low levels. SSB-2 expression was observed in the kidney and in megakaryocytes, a finding consistent with the phenotype of mice lacking this gene. Deletion of SSB-2 thus perturbs the steady-state level of two tightly controlled homeostatic parameters and identifies a critical role for SSB-2 in regulating platelet production and BUN levels.

The SOCS box of suppressor of cytokine signaling-1 is important for inhibition of cytokine action in vivo.

Suppressor of Cytokine Signaling-1 (SOCS-1) is an essential physiological inhibitor of IFN-gamma signaling. Mice lacking this gene die in the early postnatal period from a disease characterized by hyperresponsiveness to endogenous IFN-gamma. The SOCS box is a C-terminal domain shared with over 30 other proteins that links SOCS proteins to an E3 ubiquitin ligase activity and the proteasome, but whether it contributes to inhibition of cytokine signaling is currently disputed. We have deleted only the SOCS box of the SOCS-1 gene in mice and show that such mice have an increased responsiveness to IFN-gamma and slowly develop a fatal inflammatory disease. These results demonstrate that deletion of the SOCS box leads to a partial loss of function of SOCS-1.

Suppressor of cytokine signaling-3 preferentially binds to the SHP-2-binding site on the shared cytokine receptor subunit gp130.

Suppressor of cytokine signaling-3 (SOCS-3) is one member of a family of intracellular inhibitors of signaling pathways initiated by cytokines that use, among others, the common receptor subunit gp130. The SH2 domain of SOCS-3 has been shown to be essential for this inhibitory activity, and we have used a quantitative binding analysis of SOCS-3 to synthetic phosphopeptides to map the potential sites of interaction of SOCS-3 with different components of the gp130 signaling pathway. The only high-affinity ligand found corresponded to the region of gp130 centered around phosphotyrosine-757 (pY757), previously shown to be a docking site for the tyrosine phosphatase SHP-2. By contrast, phosphopeptides corresponding to other regions within gp130, Janus kinase, or signal transducer and activator of transcription proteins bound to SOCS-3 with weak or undetectable affinity. The significance of pY757 in gp130 as a biologically relevant SOCS-3 docking site was investigated by using transfected 293T fibroblasts. Although SOCS-3 inhibited signaling in cells transfected with a chimeric receptor containing the wild-type gp130 intracellular domain, inhibition was considerably impaired for a receptor carrying a Y-->F point mutation at residue 757. Taken together, these data suggest that the mechanism by which SOCS-3 inhibits the gp130 signaling pathway depends on recruitment to the phosphorylated gp130 receptor, and that some of the negative regulatory roles previously attributed to the phosphatase SHP-2 might in fact be caused by the action of SOCS-3.

Suppressors of cytokine signaling (SOCS): negative regulators of signal transduction.

SOCS-1 was originally identified as an inhibitor of interleukin-6 signal transduction and is a member of a family of proteins (SOCS-1 to SOCS-7 and CIS) that contain an SH2 domain and a conserved carboxyl-terminal SOCS box motif. Mutation studies have established that critical contributions from both the amino-terminal and SH2 domains are essential for SOCS-1 and SOCS-3 to inhibit cytokine signaling. Inhibition of cytokine-dependent activation of STAT3 occurred in cells expressing either SOCS-1 or SOCS-3, but unlike SOCS-1, SOCS-3 did not directly interact with or inhibit the activity of JAK kinases. Although the conserved SOCS box motif appeared to be dispensable for SOCS-1 and SOCS-3 action when overexpressed, this domain interacts with elongin proteins and may be important in regulating protein turnover. In gene knockout studies, SOCS-1(-/-) mice were born but failed to thrive and died within 3 weeks of age with fatty degeneration of the liver and hemopoietic infiltration of several organs. The thymus in SOCS-1(-/-) mice was small, the animals were lymphopenic, and deficiencies in B lymphocytes were evident within hemopoietic organs. We propose that the absence of SOCS-1 in these mice prevents lymphocytes and liver cells from appropriately controlling signals from cytokines with cytotoxic side effects.

Differential ability of SOCS proteins to regulate IL-6 and CSF-1 induced macrophage differentiation.

M1/WT4 cells, derived from the murine myeloid leukemic M1 cells by over-expression of the receptor for CSF-1, were transfected with expression vectors encoding SOCS-1, SOCS-2, SOCS-3 or Cis-1. The differentiation response to CSF-1 and IL-6 was analyzed in the resulting cell lines. Myeloid differentiation in response to CSF-1 was not affected by any of the SOCS proteins, whereas the IL-6-mediated differentiation was inhibited by SOCS-1 and SOCS-3 and slightly delayed by SOCS-2 expression. In M1/WT4 cells IL-6 causes strong tyrosine phosphorylation of STAT3, whereas the response to CSF-1 is weaker. The expression of the SOCS proteins had no effect on CSF-1 mediated STAT3 tyrosine phosphorylation; however, SOCS-1 and SOCS-3 reduced the tyrosine phosphorylation of STAT3 in response to IL-6 but did not abolish it. It appears, therefore, that SOCS-1, -2 and -3 and Cis-1 do not inhibit tyrosine kinase activity involved in CSF-1 mediated cell differentiation, whereas SOCS-1 and -3 are inhibiting kinase activity required for IL-6-mediated differentiation.

The carboxyl-terminal domains of gp130-related cytokine receptors are necessary for suppressing embryonic stem cell differentiation. Involvement of STAT3.

Cell type-specific responses to the leukemia inhibitory factor (LIF)/interleukin 6 cytokine family are mediated by dimerization of the LIF receptor alpha-chain (LIFRalpha) with the signal transducer gp130 or of two gp130 molecules followed by activation of the JAK/STAT and Ras/mitogen-activated protein kinase cascades. In order to dissect the contribution of gp130 and LIFRalpha individually, chimeric molecules consisting of the extracellular domain of the granulocyte colony stimulating factor receptor (GCSF-R) and various mutant forms of the cytoplasmic domains of gp130 or LIFRalpha were expressed in embryonic stem (ES) cells to test for suppression of differentiation, or in a factor-dependent plasma cytoma cell line to assess for induction of proliferation. Carboxyl-terminal domains downstream of the phosphatase (SHP2)-binding sites were dispensable for mitogen-activated protein kinase activation and the transduction of proliferative signals. Moreover, carboxyl-terminal truncation mutants which lacked intact Box 3 homology domains showed decreased STAT3 activation, failed to induce Hck kinase activity and suppress ES cell differentiation. Moreover, STAT3 antisense oligonucleotides impaired LIF-dependent inhibition of differentiation. Substitution of the tyrosine residue within the Box 3 region of the GSCF-R abolished receptor-mediated suppression of differentiation without affecting the transduction of proliferative signals. Thus, distinct cytoplasmic domains within the LIFRalpha, gp130, and GCSF-R transduce proliferative and differentiation suppressing signals.

The conserved SOCS box motif in suppressors of cytokine signaling binds to elongins B and C and may couple bound proteins to proteasomal degradation.

The suppressors of cytokine signaling (SOCS) family of proteins act as intracellular inhibitors of several cytokine signal transduction pathways. Their expression is induced by cytokine activation of the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway and they act as a negative feedback loop by subsequently inhibiting the JAK/STAT pathway either by direct interaction with activated JAKs or with the receptors. These interactions are mediated at least in part by the SH2 domain of SOCS proteins but these proteins also contain a highly conserved C-terminal homology domain termed the SOCS box. Here we show that the SOCS box mediates interactions with elongins B and C, which in turn may couple SOCS proteins and their substrates to the proteasomal protein degradation pathway. Analogous to the family of F-box-containing proteins, it appears that the SOCS proteins may act as adaptor molecules that target activated cell signaling proteins to the protein degradation pathway.

Mutational analyses of the SOCS proteins suggest a dual domain requirement but distinct mechanisms for inhibition of LIF and IL-6 signal transduction.

SOCS-1 (suppressor of cytokine signaling-1) is a representative of a family of negative regulators of cytokine signaling (SOCS-1 to SOCS-7 and CIS) characterized by a highly conserved C-terminal SOCS box preceded by an SH2 domain. This study comprehensively examined the ability of several SOCS family members to negatively regulate the gp130 signaling pathway. SOCS-1 and SOCS-3 inhibited both interleukin-6 (IL-6)- and leukemia inhibitory factor (LIF)-induced macrophage differentiation of murine monocytic leukemic M1 cells and LIF induction of a Stat3-responsive reporter construct in 293T fibroblasts. Deletion of amino acids 51-78 in the N-terminal region of SOCS-1 prevented inhibition of LIF signaling. The SOCS-1 and SOCS-3 N-terminal regions were functionally interchangeable, but this did not extend to other SOCS family members. Mutation of SH2 domains abrogated the ability of both SOCS-1 and SOCS-3 to inhibit LIF signal transduction. Unlike SOCS-1, SOCS-3 was unable to inhibit JAK kinase activity in vitro, suggesting that SOCS-1 and SOCS-3 act on the JAK-STAT pathway in different ways. Thus, although inhibition of signaling by SOCS-1 and SOCS-3 requires both the SH2 and N-terminal domains, their mechanisms of action appear to be biochemically different.

The SOCS proteins: a new family of negative regulators of signal transduction.

The negative regulation of cytokine signaling, with the exception of the tyrosine phosphatases, is not widely understood. We recently identified a new family of negative regulators by retroviral expression of hematopoietic cDNA library in the monocytic leukemic cell line, M1. This was coupled with selection for cells that were no longer able to differentiate in response to interleukin-6. From this screen, SOCS-1 was cloned and was shown to arrest cytokine signaling by binding to and inhibiting the intrinsic enzymatic activity of the JAK family of protein tyrosine kinases. SOCS-1 expression is induced in response to a range of cytokines and as such is thought to form part of a classic negative feedback loop. The SOCS family of proteins is linked by the presence of a conserved carboxy-terminal domain termed the SOCS box and now encompasses five distinct protein groups on the basis of the structural elements found amino-terminal to the SOCS box: (1) those that contain SH2 domains, (2) those that contain WD-40 repeats, (3) ankyrin repeats, (4) SPRY domains, and (5) GTPase domains. As yet the function of the SOCS box remains unknown, but given the level of conservation within such diverse proteins, it is likely to have a broadly similar role in each.

Twenty proteins containing a C-terminal SOCS box form five structural classes.

The four members of the recently identified suppressor of cytokines signaling family (SOCS-1, SOCS-2, SOCS-3, and CIS, where CIS is cytokine-inducible SH2-containing protein) appear, by various means, to negatively regulate cytokine signal transduction. Structurally, the SOCS proteins are composed of an N-terminal region of variable length and amino acid composition, a central SH2 domain, and a previously unrecognized C-terminal motif that we have called the SOCS box. By using the SOCS box amino acid sequence consensus, we have searched DNA databases and have identified a further 16 proteins that contain this motif. These proteins fall into five classes based on the protein motifs found N-terminal of the SOCS box. In addition to four new SOCS proteins (SOCS-4 to SOCS-7) containing an SH2 domain and a SOCS box, we describe three new families of proteins that contain either WD-40 repeats (WSB-1 and -2), SPRY domains (SSB-1 to -3) or ankyrin repeats (ASB-1 to -3) N-terminal of the SOCS box. In addition, we show that a class of small GTPases also contains a SOCS box. The expression of representative members of each class of proteins differs markedly, as does the regulation of expression by cytokines. The function of the WSB, SSB, and ASB protein families remains to be determined.

Neutralising antibodies to the granulocyte colony-stimulating factor receptor recognise both the immunoglobulin-like domain and the cytokine receptor homologous domain.

To define regions of the granulocyte colony-stimulating factor (G-CSF) receptor that are important for ligand binding, neutralising monoclonal antibodies to the human receptor have been produced. Eleven antibodies recognised six different receptor epitopes. Antibodies from three of the epitope groups were able to detect the receptor by western blotting but did not inhibit G-CSF binding. The other three antibody groups inhibited G-CSF binding either completely (groups 1 and 2) or partially (group 3). All the antibodies inhibited proliferation of BA/F3 cells expressing the G-CSF receptor to varying extents. By using human-marine chimeric receptors, the binding sites of the antibodies were mapped to the immunoglobulin-like domain (groups 1 and 3), the cytokine receptor homologous domain (group 2) or the fibronectin type III domains (groups 4 to 6). These results show that the immunoglobulin-like and cytokine receptor homologous domains of the receptor are important for ligand binding and subsequent signalling.

Tyrosine residues in the granulocyte colony-stimulating factor (G-CSF) receptor mediate G-CSF-induced differentiation of murine myeloid leukemic (M1) cells.

The cytoplasmic tyrosine residues of many growth factor receptors have been shown to be important for receptor signal transduction via the recruitment of proteins containing phosphotyrosine-binding domains. This study demonstrates the importance of specific tyrosine residues in the granulocyte colony-stimulating factor (G-CSF) receptor cytoplasmic domain in G-CSF-induced macrophage cell differentiation. Site-directed mutagenesis was used to generate a series of G-CSF receptor (G-CSF-R) mutants in which the tyrosine residues were replaced with phenylalanine either singly or in combination. The mouse myeloid leukemic cell line (M1) transfected with G-CSF-R cDNA can be induced to differentiate into macrophages in response to G-CSF. The effect of the tyrosine mutations on this differentiation response was assessed by examining cell morphology and differentiation in soft agar colony assays. Although three of the four cytoplasmic tyrosine residues appeared to contribute to the differentiation response, mutation of a single residue (Tyr744) significantly reduced the ability of the M1 cells to differentiate. The STAT family of signaling molecules (Stat1, Stat3, and Stat5) were activated by G-CSF in M1 cells expressing those G-CSF-R tyrosine mutants unable to mediate G-CSF-induced differentiation. Furthermore, activation of STAT proteins was shown to occur in the absence of all four cytoplasmic tyrosine residues, suggesting an alternative mechanism for STAT activation other than direct interaction with receptor phosphotyrosines.

Distinct regions of the granulocyte colony-stimulating factor receptor are required for tyrosine phosphorylation of the signaling molecules JAK2, Stat3, and p42, p44MAPK.

The protein tyrosine kinases JAK1 and JAK2 are phosphorylated tyrosine after the interaction of granulocyte colony-stimulating factor (G-CSF) with its transmembrane receptor. So too is Stat3, a member of the STAT family of transcriptional activators thought to be activated by the JAK kinases. Truncated G-CSF receptor (G-CSF-R) mutants were used to determine the different regions of the cytoplasmic domain necessary for tyrosine phosphorylation of the signaling molecules JAK2, Stat3, and p42, p44MAPK. We have shown that G-CSF-induced tyrosine phosphorylation and kinase activation of JAK2 requires the membrane proximal 57 amino acids of the cytoplasmic domain. In contrast, maximal Stat3 tyrosine phosphorylation required amino acids 96 to 183 of the G-CSF-R cytoplasmic domain, Stat3 DNA binding could occur with a receptor truncated 96 amino acids from the transmembrane domain and containing a single tyrosine residue, but was reduced in comparison with the full-length receptor. Together with the tyrosine phosphorylation of Stat3, this finding suggests that additional Stat3 does not appear to be required for proliferation. MAP kinase tyrosine phosphorylation correlated with both the proliferative response and JAK2 activation.

Tyrosine kinase JAK1 is associated with the granulocyte-colony-stimulating factor receptor and both become tyrosine-phosphorylated after receptor activation.

Granulocyte-colony-stimulating factor (G-CSF) stimulates the proliferation and differentiation of cells of the neutrophil lineage by interaction with a specific receptor. Early signal transduction events following G-CSF receptor activation were studied. We detected tyrosine phosphorylation of both the G-CSF receptor and the protein tyrosine kinase JAK1 following G-CSF binding to the human G-CSF receptor. In vitro, the kinase activity of JAK1 was increased by G-CSF stimulation. Coimmunoprecipitation of JAK1 with the G-CSF receptor suggested a physical association which existed prior to G-CSF stimulation.

The growth of carcinogen-induced colon cancer in rats is inhibited by cimetidine.

Colon cancer was induced in 40 Sprague Dawley rats using a 10-week course of 1,2 dimethylhydrazine (DMH). Twenty animals received cimetidine in their drinking water, commencing 5 weeks after concluding the course of DMH. After five weeks treatment of the animals were sacrificed and the colon and rectum excised. Tumours were assessed histologically for depth of invasion, inflammatory cell response and stained for Proliferating Cell Nuclear Antigen (PCNA), as a measure of tumour proliferative index. PCNA staining was measured using a computerized image analysis system. There were 25 tumours in the cimetidine treated group and 20 in controls. In the control group, 10% of the tumours were benign, 35% malignant polyps, 40% invading through submucosa and 15% invading through the bowel wall, as opposed to 40%, 44%, 8% and 8%, respectively in the cimetidine group (Chi squared test: P = 0.002). The mean proliferative index for control tumours was 27.9% and for the cimetidine tumours 23.1% t test: P = 0.002). It is concluded that cimetidine inhibits colon cancer cellular proliferation and slows early tumour invasion in this animal model.

Glucose repression of pigment production in atypical isolates of Aeromonas salmonicida responsible for goldfish ulcer disease.

The effect of glucose and other carbohydrates on the pigmentation of three atypical isolates of Aeromonas salmonicida indicated that the addition of D-glucose at a concentration of 0.1% (w/v) or more, inhibited pigment production and caused a reduction in the size of colonies. The addition of cAMP reversed the inhibitory effects of D-glucose on pigment production.