Kallikreins are associated with secondary progressive multiple sclerosis and promote neurodegeneration

Abstract

Tissue kallikrein KLK1 and the kallikrein-related peptidases KLK2-15 are a subfamily of serine proteases that have defined or proposed roles in a range of central nervous system (CNS) and non-CNS pathologies. To further understand their potential activity in multiple sclerosis (MS), serum levels of KLK1, 6, 7, 8 and 10 were determined in 35 MS patients and 62 controls by quantitative fluorometric ELISA. Serum levels were then correlated with Expanded Disability Status Scale (EDSS) scores determined at the time of serological sampling or at last clinical follow-up. Serum levels of KLK1 and KLK6 were elevated in MS patients (p<or=0.027), with highest levels associated with secondary progressive disease. Elevated KLK1 correlated with higher EDSS scores at the time of serum draw and KLK6 with future EDSS worsening in relapsing remitting patients (p<or=0.007). Supporting the concept that KLK1 and KLK6 promote degenerative events associated with progressive MS, exposure of murine cortical neurons to either kallikrein promoted rapid neurite retraction and neuron loss. These novel findings suggest that KLK1 and KLK6 may serve as serological markers of progressive MS and contribute directly to the development of neurological disability by promoting axonal injury and neuron cell death.

Modulation of Macrophage Infiltration and Inflammatory Activity by the Phosphatase SHP-1 in Virus-Induced Demyelinating Disease

“…For instance, macrophages have been identified as the major responders to CNS chemokines and producers of a number of proinflammatory cytokines, chemokines, and toxic molecules known to promote demyelination (32,44,63,85,90,91,93,103). Interestingly, both the brains of MS patients and the brains of experimental animals with MS-like diseases contain activated transcription factors like NF-B (34, 40), STAT1 (35,37,40), and STAT6 (18,21,109), which can lead to enhanced expression of these inflammatory molecules.…”

The use of kallikrein-related peptidases as adjuvant prognostic markers in colorectal cancer

“…Human tissue kallikrein-related peptidases (KLKs) are a family of 15 serine proteases with diverse physiological functions. KLKs play important roles in different physiologic processes such as regulation of cell growth and differentiation, tissue remodelling, angiogenesis , skin desquamation, human semen liquefaction (Pampalakis and Sotiropoulou, 2007), dental enamel formation (Lu et al, 2008), neuro-degeneration (Scarisbrick et al, 2008), inflammation (Oikonomopoulou et al, 2007), cervico-vaginal physiology (Shaw and Diamandis, 2008), and vascularisation (Smith et al, 2008). So far, KLKs have been widely examined as cancer biomarkers, mostly in steroidhormone-regulated cancers (Emami and Diamandis, 2007), because steroid hormones play an important role in the regulation of kallikrein transcription (Paliouras et al, 2007).…”

Activation profiles of human kallikrein‐related peptidases by proteases of the thrombostasis axis

“…Furthermore, the KLK1-kinin system, which influences the permeability of the blood-brain barrier, is activated in stroke (Wagner et al 2002). Given the growing evidence supporting coincident alterations in KLKs and thrombostasis enzymes in a range of CNS disorders, including Alzheimer's (Zarghooni et al 2002;Paul et al 2007), stroke (Chao and Chao 2006;Gravanis and Tsirka 2008), trauma (Festoff et al 2004;Scarisbrick et al 2006b), and MS (Gveric et al 2001;Scarisbrick et al 2002Scarisbrick et al , 2008Terayama et al 2005), there appears to be tremendous potential for the intersection of these two important protease families. KLK6 is up-regulated in response to CNS damage and in concert with the demyelination/remyelination processes that take place after such damage (Scarisbrick et al 1997;He et al 2001;Terayama et al 2004).…”

“…It is of considerable interest with regard to the potential interaction between KLK6 and plasmin that plasmin inhibitors, like those for KLK6, have been shown to slow the progress of EAE (Brosnan et al 1980). Tissue kallikrein (KLK1) is known to be activated within CNS in stroke (Wagner et al 2002) and elevated in the serum of MS patients (Scarisbrick et al 2008). Additionally, activation of both plasma and tissue kallikreins occurs during activation of the contact system after cardiopulmonary bypass (Campbell et al 2001).…”

“…Evidence suggests several other KLKs are differentially regulated in specific types of cancer (Clements 1989;Diamandis et al 2000;Pampalakis and Sotiropoulou 2007;Ramsay et al 2008;Singh et al 2008) and may also be potentially useful as cancer biomarkers Clements et al 2004). Additionally, KLK family members have been shown to be intimately associated with physiological processes of skin desquamation (Lundstrom and Egelrud 1991;Brattsand and Egelrud 1999;Brattsand et al 2005), inflammatory demyelination (Blaber et al 2004;Scarisbrick et al 2006a), neurodegeneration (Scarisbrick et al 2008), and semen liquefaction (Kumar et al 1997;Vaisanen et al 1999;Malm et al 2000;Michael et al 2006). These lines of evidence point to the increasing importance of KLKs in the diagnosis and treatment of serious human medical disorders.…”