GOT C1 Inhibitor?

As the soldiers of the Knight’s Watch gazed down in horror, the 800 foot tall ice wall that has protected the seven kingdoms for a thousand years comes under attack by the Night King astride his fire-breathing, un-dead dragon.  With each successive burst of devastating hellfire, the wall weakens, shatters, and finally collapses giving way to streaming hoards of hideous Wight zombie soldiers commanded by ferocious White Walkers destined to exterminate, and then assimilate all beings in their path into the legion of the un-dead.

As true fans of Game of Thrones are well aware, this climactic scene concludes the penultimate season finale and forebodes the havoc that awaits in the final chapter of this epic tale.  Amidst the chaos, the intrepid and long-suffering Jon Snow bravely attempts to negotiate the balance of power between warring factions to marshal their forces for the ultimate goal… the survival of the living (mankind).

So you may ask, what does this have to do with C1-inhibitor?  For that matter, what is C1-inhibitor? 

Well, metaphorically speaking, C1-inhibitor (aka complement 1-esterase inhibitor) is one of a number of proteins that serve the purpose of being a wall guardian or gate keeper, so to speak.  This multifunctional protein is involved the responses to outside invaders, such as microbial pathogens, as well as maintaining the integrity of the vascular system.  This protein is the primary regulator of the contact system by inactivating plasma kallikrein and coagulation factor XIIa.  By inhibiting kallikrein and the subsequent generation of bradykinin, C1-INH serves to maintain the integrity of the vascular “wall”.   Its absence, mutation or inactivation therefore results in excessive vascular permeability, as observed in the condition known as hereditary angioedema (HAE).

C1-INH is the only physiological inhibitor of classical complement cascade activation (C1s and C1r proteases).  It also exerts regulatory effects over the coagulation system through its participation in the inhibition of factor XI and thrombin.  It is an integral protein in the regulation of the fibrinolytic cascade via its ability to inactivate plasmin and tissue plasminogen activator (tPA).  As such, this versatile protein it is an excellent therapeutic target for the treatment of sepsis, ischemia-reperfusion injury, ischemic brain injury, and myocardial infarction, and is currently used for combating the effects of HAE (1).

C1-inhibitor activity appears to be involved with maintaining integrity of another physiological wall:  the blood-brain barrier (BBB). Indeed, the degradation of C1-inhibitor activity can lead to increased permeability of the BBB, leaving the nervous system vulnerable to invasion by microorganisms, harmful proteins such as inflammatory cytokines, and destructive oxidative radicals (2).  More recently, it has been demonstrated that lower expression levels of C1-inhibitor have been associated with accumulation of amyloid fibrils in Alzheimer’s disease (3).  And though activation of the complement cascade was once thought just to function in removal of malignant cells, more recent evidence supports a role in the activation of cancer-enhancing signal pathways (4).  Indeed, administration of C1-inhibitor is being investigated as an anti-cancer therapy.

Molecular Innovations has developed a genetically modified knockout  mouse strain that is deficient in C1-inhibitor.  We offer mice that are either heterozygous or homozygous for a large deletion encompassing the majority of the Serping1 (C1-inhibitor) gene.  These mice appear normal, demonstrating no apparent ill effects, but exhibit vascular permeability in Evan’s blue experiments.  This mouse strain should prove to be a valuable tool in the study of HAE, inflammation, cancer, and Alzheimer’s disease to name a few potential applications.

In addition, we offer sensitive ELISA assay kits for human C1-inhibitor, components of the complement cascade, inflammation-related proteins, as well as recombinant murine C1-inhibitor and many other unique and valuable research tools.  Be sure to sign up for our newsletter you that you too can stay “on watch”!

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Further Reading:

  1. Karnaukhova, E.  C1-esterase inhibitor:  Biologial activities and therapeutic applications.  J. Hematol. Thromb. Dis.  (2013) 1:113.
  2. Veerhuis R, Janssen I, Hoozemans JJ, De Groot CJ, Hack CE, Eikelenboom P. Complement C1-inhibitor expression in Alzheimer’s disease.  Acta Neuropathol. 1998), 96:287-96.
  3. Zamolodchikov D., Renné, T., Strickland, S. The Alzheimer’s disease peptide β-amyloid promotes thrombin generation through activation of coagulation factor XII. J Thromb Haemost. (2016) 14:995-1007.
  4. Pio, R., Ajona, D., Lambris, J.D. Complement inhibition in cancer therapy. Semin. Immunol. (2013) 25:54-64.
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