Concept: Glycoprotein 130
Oncostatin M (OSM) is an inflammatory cytokine which interacts with a heterodimeric receptor formed by gp130 and either OSMRβ or LIFR. Here we have analysed OSM and its receptors in livers with chronic hepatitis C (CHC) and studied the factors that regulate this system.
Multiple cytokines, including interleukin 6 (IL-6), IL-11, IL-27, oncostatin M (OSM), and leukemia inhibitory factor (LIF), signal via the common GP130 cytokine receptor subunit. In this study, we describe a patient with a homozygous mutation of IL6ST (encoding GP130 p.N404Y) who presented with recurrent infections, eczema, bronchiectasis, high IgE, eosinophilia, defective B cell memory, and an impaired acute-phase response, as well as skeletal abnormalities including craniosynostosis. The p.N404Y missense substitution is associated with loss of IL-6, IL-11, IL-27, and OSM signaling but a largely intact LIF response. This study identifies a novel immunodeficiency with phenotypic similarities to STAT3 hyper-IgE syndrome caused by loss of function of GP130.
Oncostatin M (OSM) is produced by activated T cells, monocytes, and dendritic cells and signals through two distinct receptor complexes consisting of gp130 and LIFR (I) or OSMR-β and gp130 (II), respectively. Aim of this study was to analyze the role of OSM in intestinal epithelial cells (IEC) and intestinal inflammation.
Interleukin (IL-)6 is the major pro-inflammatory cytokine within the IL-6 family. IL-6 signals via glycoprotein 130 (gp130) and the membrane-bound or soluble IL-6 receptor (IL-6R), referred to as classic or trans-signaling, respectively. Whereas inflammation triggers IL-6 expression, eventually rising to nanogram per mL serum levels, soluble IL-6R (sIL-6R) and soluble gp130 (sgp130) are constitutively present in the upper nanogram per mL range. Calculations based on intermolecular affinities have suggested that systemic IL-6 is immediately trapped in IL-6:sIL-6R and IL-6:sIL-6R:sgp130 complexes, indicating that sIL-6R and sgp130 constitute a buffer system that increases the serum half-life of IL-6 or restricts systemic IL-6 signaling. However, this scenario has not been experimentally validated. Here, we quantified IL-6:sIL-6R and IL-6:sIL-6R:sgp130 complexes over a wide concentration range. The amounts of IL-6 used in this study reflect concentrations found during active inflammatory events. Our results indicated that most IL-6 is free and not complexed with sIL-6R or sgp130, indicating that the level of endogenous sgp130 in the bloodstream is not sufficient to block IL-6 trans-signaling via sIL-6R. Importantly, addition of the single-domain antibody VHH6, which specifically stabilizes IL-6:sIL-6R complexes but did not bind to IL-6 or sIL-6R alone, drove free IL-6 into IL-6:sIL-6R complexes and boosted trans-signaling but not classic signaling, demonstrating that endogenous sIL-6R has a least the potential to form complexes with IL-6 . Our findings indicate that even though high concentrations of sIL-6R and sgp130 are present in human serum, the relative ratio of free IL-6 to IL-6:sIL-6R allows for simultaneous classic and trans-signaling.
Oncostatin M (OSM) and leukemia inhibitory factor (LIF) are closely related members of the interleukin-6 (IL-6) cytokine family. Both cytokines share a common origin and structure, and both interact through a specific region, termed binding site III, to activate a dimeric receptor complex formed by glycoprotein 130 (gp130) and LIF receptor (LIFR) in humans. However, only OSM activates the OSM receptor (OSMR)/gp130 complex. The molecular features that enable OSM to specifically activate the OSMR are currently unknown.
To define specific sequence motifs within OSM that are critical for initiating signaling via OSMR, here we generated chimeric OSM-LIF cytokines and performed alanine-scanning experiments. Replacement of the OSM AB loop within OSM’s binding site III with that of LIF abrogated OSMR activation, measured as STAT3 phosphorylation at Tyr-705, but did not compromise LIFR activation. Correspondingly, substitution of the AB loop and D-helix in LIF with their OSM counterparts was sufficient for OSMR activation. The alanine-scanning experiments revealed that residues Tyr-34, Gln-38, Gly-39 and Leu-45 (in the AB loop) and Pro-153 (in the D-helix) had specific roles in activating OSMR but not LIFR signaling, while Leu-40 and Cys-49 (in the AB loop), and Phe-160 and Lys-163 (in the D-helix) were required for activation of both receptors. Since most of the key amino acid residues identified here are conserved between LIF and OSM, we concluded that comparatively minor differences in a few amino acid residues within binding site III account for the differential biological effects of OSM and LIF.
Oncostatin M (OSM) is an inflammatory cytokine of the gp130 family. OSM could participate in adverse cardiovascular remodeling through regulation of FGF23.
- Journal of musculoskeletal & neuronal interactions
- Published almost 2 years ago
To explore the effects of protein factor Oncostatin M (OSM), a member of the Interleukin-6 (IL-6) family on cell proliferation, osteogenic differentiation and mineralization.
Oncostatin M (OSM) and leukemia inhibitory factor (LIF) are IL-6 family members with a wide range of biological functions. Human OSM (hOSM) and murine LIF (mLIF) act in mouse cells via a LIF receptor (LIFR): glycoprotein 130 (gp130) heterodimer. In contrast, murine OSM (mOSM) signals mainly via an OSM receptor (OSMR):glycoprotein 130 (gp130) heterodimer, and binds with only very low affinity to mLIFR. hOSM and mLIF stimulate bone remodelling both by reducing osteocytic sclerostin and upregulating the pro-osteoclastic factor RANKL in osteoblasts. In the absence of OSMR, mOSM still strongly suppressed sclerostin and stimulated bone formation but did not induce RANKL suggesting that intracellular signalling activated by the low-affinity interaction of mOSM with mLIFR is different to the downstream effects when mLIF or hOSM interact with the same receptor. Both STAT1 and STAT3 were activated by mOSM in wildtype cells or by mLIF/hOSM in wildtype and Osmr-/- cells. In contrast, in Osmr-/- primary osteocyte-like cells stimulated with mOSM (therefore acting through mLIFR), microarray expression profiling and Western blot analysis identified preferential phosphorylation of STAT3 and induction of its target genes but not of STAT1 and its target genes; this correlated with reduced phosphorylation of both gp130 and LIFR. In a mouse model of spontaneous osteopenia caused by hyperactivation of STAT1/3 signalling downstream of gp130 (gp130Y757F/Y757F), STAT1 deletion rescued the osteopenic phenotype, indicating a beneficial effect of promoting STAT3 signalling over STAT1 downstream of gp130 in this low bone mass condition, and this may have therapeutic value.
- The Journal of neuroscience : the official journal of the Society for Neuroscience
- Published about 3 years ago
Cell-surface receptors provide potential targets for the translation of bench-side findings into therapeutic strategies; however, this approach for the treatment of stroke is disappointing, at least partially due to an incomplete understanding of the targeted factors. Previous studies of oncostatin M (OSM), a member of the gp130 cytokine family, have been limited, as mouse models alone may not strongly resemble the human condition enough. In addition, the precise function of OSM in the CNS remains unclear. Here, we report that human OSM is neuroprotective in vivo and in vitro by recruiting OSMRβ in the setting of ischemic stroke. Using gain- and loss-of-function approaches, we demonstrated that decreased neuronal OSMRβ expression results in deteriorated stroke outcomes but that OSMRβ overexpression in neurons is cerebroprotective. Moreover, administering recombinant human OSM to mice before the onset of I/R showed that human OSM can be protective in rodent models of ischemic stroke. Mechanistically, OSM/OSMRβ activate the JAK2/STAT3 prosurvival signaling pathway. Collectively, these data support that human OSM may represent a promising drug candidate for stroke treatment.
To investigate whether eutopic endometrial expression of leukaemia inhibitory factor (LIF), LIF receptor (LIFR) and glycoprotein 130 (gp130) in subfertile women with endometriosis and in healthy controls is related to the probability of spontaneous pregnancy. In addition, we aimed to study peritoneal fluid (PF) levels of interleukin (IL)-1α and IL-6 in the same subsets of women.