Search results

Bronchoalveolar lavage fluid from mice with experimentally induced allergic pulmonary inflammation contains a novel 9.4 kDa cysteine-rich secreted protein, RELM-alpha (FIZZ1, found in inflammatory zone). RELM-alpha is a secreted protein that has a restricted tissue distribution with highest levels in adipose tissue stroma. Murine RELM-alpha (FIZZ1) is the founding member of a new gene family including two other murine genes expressed, respectively, in intestinal crypt epithelium (RELM-beta) and white adipose tissue (Resistin), and two related human genes.
RELMalpha inhibits the differentiation of 3T3-L1 preadipocytes into adipocytes but has no effect on proliferation of 3T3-L1 preadipocytes. RELMalpha is able to form heterooligomers with resistin but not RELMbeta. Since RELMalpha is expressed by adipose tissue and it is a secreted factor, our findings suggest that RELMalpha may be involved in the control of the adipogenesis as well as in the process of muscle differentiation.
In the lung, RELM-alpha is induced by hypoxia and was renamed as hypoxia-induced mitogenic factor (HIMF). HIMF strongly activated Akt phosphorylation. The phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 (10 micromol/L) inhibited HIMF-activated Akt phosphorylation. It also inhibited HIMF stimulated RPSM proliferation. Thus, the PI3K/Akt pathway, at least in part, mediates the proliferative effect of HIMF. Further studies showed that HIMF had angiogenic and vasoconstrictive properties. HIMF increased pulmonary arterial pressure and vascular resistance. Further studies suggest that HIMF regulates apoptosis and may participate in lung alveolarization and maturation.

RELM-gamma is a novel member of the resistin-like molecule/found in inflammatory zone (RELM/FIZZ) family in mice and rats. Microarray and real-time RT-PCR experiments revealed a repression of RELMgamma mRNA in nasal respiratory epithelium of cigarette smoke-exposed versus untreated rats. The analysis of the physiological tissue-specific expression revealed highest expression in hematopoietic tissues, suggesting a cytokine-like role for RELM-gamma. RELM-gamma-mRNA is detectable in bone marrow, spleen, and lung as well as in peripheral blood granulocytes. Promyelocytic HL60 cells transfected with a RELM-gamma expression plasmid have an increased proliferation rate compared to mock-transfected cells and display an altered response to retinoic acid-induced granulocytic differentiation. Taken together, these data provide the first experimental evidence that RELM-gamma is a secreted molecule with a restricted expression pattern that may play a role in promyelocytic differentiation.

Myeloid differentiation primary response gene 88 (MYD88) is a cytosolic adapter protein, which has a central role in the innate and adaptive immune response. MYD88 functions as a vital signal transducer in the interleukin-1 and Toll-like receptor signaling pathways. MYD88 acts via IRAK1, IRAK2, IRF7 and TRAF6, leading to NF-kappa-B activation, cytokine secretion and the inflammatory response. The MYD88 protein increases IL-8 transcription. MYD88 is involved in IL-18-mediated signaling pathway. MYD88 activates IRF1, resulting in its rapid migration into the nucleus to mediate an efficient induction of IFN-beta, NOS2/INOS, and IL12A genes. MYD88 is comprised of an N-terminal death domain and a C-terminal Toll-interleukin1 receptor domain. Patients with defects in the MYD88 gene have an increased susceptibility to pyogenic bacterial infections.

CD8B encodes the CD8 beta chain isoforms of the CD8 antigen. CD8 is a cell surface glycoprotein which facilitates efficient cell-cell interactions within the immune system and is located on most cytotoxic T lymphocytes. The T-cell receptor on the T lymphocyte and the co-receptor CD8 antigen identify antigens exposed by an antigen presenting cell (APC) in the context of class I MHC molecules. The functional co-receptor is either a heterodimer composed of one alpha and one beta chain or a homodimer composed of two alpha chains. Both alpha and beta chains share substantial homology to immunoglobulin variable light chains.

Uteroglobin (SCGB1A1) which belongs to the Secretoglobin (SCGBs) superfamily, is a multifunctional protein that exerts anti-inflammatory and anti-tumorigenic effects by binding small hydrophobic molecules such as phospholipids and prostaglandins. Uteroglobin is involved in numerous functions including anti-inflammation, inhibition of phospholipase A2 and the sequestering of hydrophobic ligands. SCGB1A1 is expressed by Clara cells, the non-ciliated, non-mucous secretory cells predominant in lung bronchioles, and by other epithelia which communicate with the external environment. On top of sequestering pro-inflammatory mediators and carcinogens, Uteroglobin is implicated in the inhibition of cell migration and invasion, platelet aggregation, and T cell differentiation. SCGB1A1 gene defects are associated with a susceptibility to asthma.

The cytokine Macrophage migration inhibitory factor (MIF) has been identified to be secreted by the pituitary gland and the monocyte/macrophage and to play an important role in endotoxic shock. MIF has the unique property of being released from macrophages and T cells in response to physiological concentrations of glucocorticoids. The secretion of MIF is tightly regulated and decreases at high, anti-inflammatory steroid concentration.

CFI cleaves and inactivates C3b and C4b. CFI is inactive without a cofactor such as the soluble factor H and C4b binding protein. CFI cleaves the alpha-peptide chain of C3b and C4b when these binds1 of the cofactors. This cleavage inactivates all of the complement activating functions of these proteins producing iC3b and iC4b.CFI cleaves the alpha chain of C3b twice and this releases a small fragment called C3f. CFI can cleave iC3b releasing C3c from C3dg in the presence of CR1.C4b is cleaved rapidly at 2 sites separating C4c from C4d.

IFN-gamma produced by lymphocytes activated by specific antigens or mitogens.
IFN-gamma, in addition to having antiviral activity, has important immunoregulatory functions, it is a potent activator of macrophages, and has antiproliferative effects on transformed cells and it can potentiate the antiviral and antitumor effects of the type I interferons.

MCSFR which is also familiar as CSF1R, is part of the type3 subfamily of receptor tyrosine kinases. MCSFR is expressed mainly on cells of the monocyte and macrophage lineage, stem cells, and in the growing placenta. Most of the biological effects of this cytokine are mediated by MCSFR. MCSFR contains an extracellular ligand-binding domain, a single membrane-spanning segment, and an intracellular tyrosine kinase domain. Originally CSF1 and this receptor were implicated as vital for normal trophoblastic implantation as well as monocyte development. The role of CSF1/CSF1R in normal mammary gland development is actually very interesting since this connection has also been discovered in the biology of breast cancer with the results of abnormal expression of CSF1 and its receptor. Likewise, in Alzheimer's disease and after brain injuries an increased level of CSF1R was found in the microglia, which causes the microglia to become more active.

IFN-alpha 1b is produced by macrophages, IFN-alpha 1b has antiviral activities and stimulates the production of two enzymes: a protein kinase and an oligoadenylate synthetase.

Adiponectin is a recently discovered 244 amino acid protein, the product of the apM1 gene, which is physiologically active and specifically and highly expressed in adipose cells (Adipokine). The protein belongs to the soluble defense collagen super family; it has a collagen-like domain structurally homologous with collagen VIII and X and complement factor C1q-like globular domain. APM-1 forms homotrimers, which are the building blocks for higher order complexes found circulating in serum.

Granulocyte Colony Stimulating Factor is a growth factor and/or cytokine produced by the endothelium, macrophages and a number of other immune cells. GCSF stimulates the bone marrow to produce granulocytes and also to stimulate the survival, proliferation, differentiation and function of neutrophil granulocyte progenator cells and mature neutrophils.

Resistin, a product of the RSTN gene, is a peptide hormone belonging to the class of cysteine-rich secreted proteins which is termed the RELM family, and is also described as ADSF (Adipose Tissue- Specific Secretory Factor) and FIZZ3 (Found in Inflammatory Zone). Human resistin contains 108 amino acids as a prepeptide, and its hydrofobic signal peptide is cleaved before its secretion. Resistin circulates in human blood as a dimeric protein consisting of two 92 amino acid polypeptides, which are disulfide-linked via Cys26.
Resistin may be an important link between obesity and insulin resistance. Mouse resistin, specifically produced and secreted by adipocyte, acts on skeletal muscle myocytes, hepatocytes and adipocytes themselves so that it reduces their sensitivity to insulin. Steppan et al. have suggested that resistin suppresses the ability of insulin to stimulate glucose uptake. They have also suggested that resistin is present at elevated levels in blood of obese mice, and is down regulated by fasting and antidiabetic drugs. Way et al., on the other hand, have found that resistin expression is severly suppressed in obesity and is stimulated by several antidiabetic drugs.
Other studies have shown that mouse resistin increases during the differentiation of adipocytes, but it also seems to inhibit adipogenesis. In contrast, the human adipogenic differentiation is likely to be associated with a down regulation of resistin gene expression.

GLC8 is a regulatory subunit of protein phosphatase 1 (Glc7p). GLC8 plays a role in glycogen metabolism and chromosome segregation, and regulates Glc7p activity through conformational alteration; ortholog of the mammalian protein phosphatase inhibitor 2. Under regular conditions, GLC8 triggers GLC7, but when GLC8 is over epxressed, it inhibits Glc7p function. GLC8 is activated upon phosphoylation by Pho85p complexed with four cyclins (Pcl6p, Pcl7p, Pcl8p, or Pcl10p).

Adiponectin is an adipocyte specific secreted protein that circulates in the plasma. It is induced during adipocyte differentiation and its secretion is stimulated by insulin. Mouse adiponectin shares about 83% amino acid identity with that human. Adiponectin plays a role in various physiological processes such as energy homeostasis and obesity. Adiponectin is reduced in obese humans, and decreased level is associated with insulin resistance and hyperinsulinemia.

FLT3 ligand is a receptor for the fl cytokine has a tyrosine-protein kinase activity & a growth factor that regulates proliferation of early hematopoietic cells. Flt3-Ligand synergizes with other CSFs and interleukins to induce growth and differentiation.

Tumor necrosis factor is a cytokine involved in systemic inflammation and is a member of a group of cytokines that all stimulate the acute phase reaction. TNF is mainly secreted by macrophages.
TNF causes apoptotic cell death, cellular proliferation, differentiation, inflammation, tumorigenesis and viral replication, TNF is also involved in lipid metabolism, and coagulation. TNF's primary role is in the regulation of immune cells.
Dysregulation and, in particular, overproduction of TNF have been implicated in a variety of human diseases- autoimmune diseases, insulin resistance, and cancer.

GMCSF is a cytokine that controls the production, differentiation, and function of granulocytes and macrophages. The active form of the protein is found extracellularly as a homodimer. This gene has been localized to a cluster of related genes at chromosome region 5q31, which is known to be associated with interstitial deletions in the 5q- syndrome and acute myelogenous leukemia. Other genes in the cluster include those encoding interleukins 4, 5, and 13.
GM-CSF stimulates the growth and differentiation of hematopoietic precursor cells from various lineages, including granulocytes, macrophages, eosinophils and erythrocytes.

Cytokeratin 8 (KRT8) belongs to the type II keratin family clustered on the long arm of chromosome 12. Type I and type II keratins heteropolymerize to form intermediate-sized filaments in the cytoplasm of epithelial cells. KRT8 typically dimerizes with keratin 18 to form an intermediate filament in simple single-layered epithelial cells. KRT8 has a role in retaining cellular structural integrity and also functions in signal transduction and cellular differentiation. KRT8 gene mutations cause cryptogenic cirrhosis.

AIMP1 (EMPA2 or p43) is a cytokine that is specifically induced by apoptosis, and it is involved in the control of angiogenesis, inflammation, and wound healing. The release of the AIMP1 cytokine renders the tumor-associated vasculature sensitive to tumor necrosis factor. Furthermore, AIMP1 is involved in the stimulation of inflammatory responses after proteolytic cleavage in tumor cells.

CCL23 (MIP-3) is a ligand for the CCR1chemokine receptor. CCL23 is one of several cytokine genes clustered on the q-arm of chromosome 17, in a locus containing several other CC chemokines. MIP-3 chemoattracts monocytes, resting T-lymphocytes and neutrophils, but not activated lymphocytes. Furthermore, it was shown that MIP-3 inhibits colony formation of bone marrow myeloid immature progenitors. MIP-3 is mainly expressed in lung and liver tissue, but can be also found in bone marrow and placenta, as well as in some cell lines of myeloid origin.
Alternative splicing of the CCL23 gene produces 2 mRNAs which encode a short (CK?8) and a long (CK?81) isoform of the MIP-3. CK?8 cDNA encodes a 120 amino acid residue precursor protein with a putative 21 a.a. residue signal peptide which is cleaved to generate a 99 a.a. residue mature CK?8 (a.a. 22-120). Further N-terminal processing of the 99 a.a. residue variant can produce a 75 a.a. residue CK?8 (a.a. 46-120) which is considerably more active than the 99 a.a. residue variant.
MIP-3 may be involved in the malignant progression of certain human cancer cells which overexpress ErbB2 through the transactivation of ErbB2 tyrosine kinase. MIP-3 may also be involved in angiogenesis via upregulation of matrix metalloproteinase MMP-2 expression.

The B-lymphocyte activation antigen B7-1 provides regulatory signals for T lymphocytes as a consequence of binding to the CD28 and CTLA4 ligands of T cells CD-80 is involved in the costimulatory signal essential for t- lymphocyte activation. t-cell proliferation and cytokine production is induced by the binding of cd28 or ctla-4 to this receptor.

Cardiotrophin 1 (CT-1) is a 201 amino acid member of the interleukin-6 superfamily. It was identified by its ability to induce hypertrophic response in cardiac myocytes. CT-1 mRNA levels were found both in cardiac myocytes and in cardiac nonmyocytes. CT 1 was also detected in abundance in normal adult human lung and was expressed in both fetal and adult airway smooth muscle cells. CT 1 activates gp130 dependent signaling and stimulates the Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway to transduce hypertrophic and cytoprotective signals in cardiac myocytes.
CT 1 has also a neurotrophic function. CTF1 deficiency causes increased motoneuron cell death in spinal cord and brainstem nuclei of mice during a period between embryonic day 14 and the first postnatal week. Moreover, CT-1 is a hepatocyte survival factor that efficiently reduces hepatocellular damage in animal models of acute liver injury. Cardiotrophin 1 expression is augmented after hypoxic stimulation and it can protect cardiac cells when added either prior to simulated ischaemia or at the time of reoxygenation following simulated ischaemia. Cardiotrophin 1 can induce expression of the protective heat shock proteins (hsps) in cardiac cells.
Cardiotrophin-1 increased ventricular expression of ANP, brain natriuretic peptide (BNP) and angiotensinogen mRNA.
Cardiophin 1 levels were significantly elevated in patients with heart failure, patients with dilatative cardiomyopathy, moderate/severe mitral regurgitation, stable and unstable angina and after acute myocardial infarction.