ABSTRACT
Blood levels of the acute phase reactant C-reactive protein (CRP) are frequently measured as a clinical marker for inflammation, but the biological functions of CRP are still controversial. CRP is a phosphocholine (PC)-binding pentraxin, mainly produced in the liver in response to elevated levels of interleukin-1ß (IL-1ß) and of the IL-1ß-dependent cytokine IL-6. While both cytokines play important roles in host defense, excessive systemic IL-1ß levels can cause life-threatening diseases such as trauma-associated systemic inflammation. We hypothesized that CRP acts as a negative feedback regulator of monocytic IL-1ß maturation and secretion. Here, we demonstrate that CRP, in association with PC, efficiently reduces ATP-induced inflammasome activation and IL-1ß release from human peripheral blood mononuclear leukocytes and monocytic U937 cells. Effective concentrations are in the range of marginally pathologic CRP levels (IC50 = 4.9 µg/ml). CRP elicits metabotropic functions at nicotinic acetylcholine (ACh) receptors (nAChRs) containing subunits α7, α9, and α10 and suppresses the function of ATP-sensitive P2X7 receptors in monocytic cells. Of note, CRP does not induce ion currents at conventional nAChRs, suggesting that CRP is a potent nicotinic agonist controlling innate immunity without entailing the risk of adverse effects in the nervous system. In a prospective study on multiple trauma patients, IL-1ß plasma concentrations negatively correlated with preceding CRP levels, whereas inflammasome-independent cytokines IL-6, IL-18, and TNF-α positively correlated. In conclusion, PC-laden CRP is an unconventional nicotinic agonist that potently inhibits ATP-induced inflammasome activation and might protect against trauma-associated sterile inflammation.
Subject(s)
C-Reactive Protein/immunology , Inflammasomes/immunology , Inflammation , Adult , Aged , Biomarkers , C-Reactive Protein/pharmacology , Cells, Cultured , Cytokines/immunology , Cytokines/metabolism , Humans , Inflammasomes/metabolism , Inflammation/immunology , Inflammation/metabolism , Interleukin-1beta/immunology , Interleukin-1beta/metabolism , Male , Middle Aged , Receptors, Nicotinic/immunology , Receptors, Nicotinic/metabolism , Receptors, Purinergic P2X7/immunology , Receptors, Purinergic P2X7/metabolismABSTRACT
BACKGROUND: The high mortality rate of patients suffering from severe trauma is based not only on the mechanism of injury, but also on the higher risk for development of subsequent infections. Therefore, the early recognition of infection after severe trauma is of particular importance for patient outcome. However, early diagnosis is often masked by the consequences of the sterile, damage-triggered immune response. Our study sought to analyze the course of soluble CD14-subtype (sCD14-ST, presepsin) compared with clinically established inflammatory and infectious biomarkers in a cohort of patients with severe trauma. PATIENTS AND METHODS: Between January 2015 and February 2016, 50 patients suffering from severe trauma (Injury Severity Score [ISS] > 16) were enrolled and followed up for seven consecutive days after intensive care unit (ICU) admission. Clinical routine data, signs of infection, and the inflammatory biomarkers presepsin, C-reactive protein (CRP), procalcitonin (PCT), and interleukin-6 (IL-6) were assessed. RESULTS: Regarding the well-established biomarkers CRP, PCT, and IL-6, we observed trauma-associated alterations (day 1: CRP 13 mg/L, interquartile range [IQR] 0-129; PCT 1.1 µg/L, IQR 0-13; IL-6 108 pg/mL, IQR 29-795), which did not correlate with the clinical development of systemic inflammatory response syndrome (SIRS), whereas elevated plasma concentrations of presepsin in the clinical course were associated with the presence of SIRS (presepsin: no-SIRS vs. SIRS p = 0.03). CONCLUSION: Our study investigates systematically the kinetic of presepsin compared with established inflammatory and infectious markers after severe trauma. Presepsin is neither affected by the early post-traumatic nor the delayed immune response over seven days after trauma, making it a possible option as a diagnostic biomarker of infection worth further evaluation.
Subject(s)
Biomarkers/blood , Lipopolysaccharide Receptors/blood , Peptide Fragments/blood , Plasma/chemistry , Wound Infection/diagnosis , Wounds and Injuries/complications , Wounds and Injuries/pathology , Adult , Aged , Aged, 80 and over , C-Reactive Protein/analysis , Calcitonin/blood , Female , Humans , Interleukin-6/blood , Longitudinal Studies , Male , Middle Aged , Prospective Studies , Young AdultABSTRACT
A series of palladium, platinum and manganese di(organo)carbene complexes have been prepared from 4-chloro-N-methylquinolinone by processes that involve alkylation before or after attachment to the metal unit; the nucleophilic heteroatoms are separated from the C-donor atom by three bonds.
Subject(s)
Manganese/chemistry , Methane/analogs & derivatives , Methane/chemistry , Organometallic Compounds , Palladium/chemistry , Platinum/chemistry , Quinolones/chemistry , Crystallography, X-Ray , Hydrocarbons , Models, Molecular , Molecular Structure , Organometallic Compounds/chemical synthesis , Organometallic Compounds/chemistryABSTRACT
The highly symmetric title compound contains a Ni atom that is tetrahedrally coordinated by four alkylindium(I) ligands InC(SiMe3 )3 . The ligand InR is isolobal with carbon monoxide, and the product is thus a remarkable addition to the class of [Ni(CO)4 ] analogues.
