Enzymes and Immune System
last updated 8.25.05

The studies below show how enzymes become part of the immune system (Alpha-2-macroglobulin), working with it and facilitating its function.

An in-depth discussion of alpha-2-macroglobulin is located at:

Proteases and antiproteases in health and disease a review

1. Modulation of growth factor binding properties of alpha2-macroglobulin by enzyme therapy.

Lauer D, Muller R, Cott C, Otto A, Naumann M, Birkenmeier G. Institute of Biochemistry, University of Leipzig, Germany. Cancer Chemother Pharmacol. 2001 Jul;47 Suppl:S4-9. PMID: 11561872 [PubMed - indexed for MEDLINE]

PURPOSE: To investigate the binding of transforming growth factor-beta (TGF-beta) to human alpha2-macroglobulin upon oral treatment of patients with proteases. METHODS: Volunteers were given a cocktail of active proteinases (Phlogenzym) composed of trypsin, bromelain and the additive rutoside orally over a period of 7 days at low dose followed by a bolus application. Before and after medication plasma was immediately withdrawn and binding of 125I-TGF-beta to the proteinase inhibitor alpha2-macroglobulin was determined by electrophoresis and gamma-counting. Cell culture experiments were performed to study the effect of transformed alpha2-macroglobulin on TGF-beta-stimulated proliferation of skin fibroblasts. RESULTS: Ingestion of proteinases was found to trigger the formation of intermediate forms of alpha2-macroglobulin displaying high affinity to TGF-beta. Maximum binding of TGF-beta was observed 1-2 h after bolus ingestion, and steadily levelled off with time. In vitro experiments demonstrated that complex formation of diverse proteinases (trypsin, alpha-chymotrypsin, bromelain and plasmin) with alpha2-macroglobulin conferred binding of 125I-TGF-beta, alpha2-Macroglobulin transformed by methylamine or proteinases was found to abolish the TGF-beta effect on fibroblasts in cell culture. CONCLUSIONS: Intestinal absorption of proteinases triggers the formation of TGF-beta binding species of alpha2-macroglobulin in blood. Mediated by this process high concentrations of TGF-beta might be reduced via enhanced clearance of alpha2-macroglobulin-TGF-beta complexes. Thus, proteinase therapy may have beneficial effects in treatment of fibrosis and certain cancers accompanied by excessively high TGF-beta concentrations.

2. Oral therapy with proteolytic enzymes decreases excessive TGF-beta levels in human blood.

Desser L, Holomanova D, Zavadova E, Pavelka K, Mohr T, Herbacek I. Institute of Cancer Research, University of Vienna, Austria. Cancer Chemother Pharmacol. 2001 Jul;47 Suppl:S10-5. PMID: 11561866 [PubMed - indexed for MEDLINE]

Therapy with oral proteolytic enzymes (OET) with combination drug products containing papain, bromelain, trypsin, and chymotrypsin has been shown to be beneficial in clinical settings such as radiotherapy-induced fibrosis, bleomycin pneumotoxicity and immunosuppression in cancer, all of which are nowadays known to be accompanied by excessive transforming growth factor-beta (TGF-beta) production. It has been demonstrated that proteolytic enzymes reduce TGF-beta levels in serum by converting the protease inhibitor alpha2 macroglobulin (alpha2M) from the 'slow' form into the 'fast' form, whereby the 'fast' form binds and inactivates TGF-beta irreversibly. In this study we have investigated the effect of OET on the concentration of TGF-beta1 in serum of patients with rheumatoid arthritis (RA) (n = 38), osteomyelofibrosis (OMF) (n = 7) and herpes zoster (HZ) (n = 7). Seventy-eight healthy volunteers served as controls. TGF-beta1 levels in serum were assessed by enzyme-linked immunosorbent assay (ELISA). We have demonstrated that in healthy volunteers and in patients there exists a correlation between active and latent TGF-beta1 in serum (r=0.8021; P<0.0001). Treatment with OET had no significant effect on TGF-beta1 concentration in healthy volunteers or patients with a normal level of TGF-beta1. In patients with elevated TGF-beta1 concentration (> 50 ng/ml serum), OET reduced TGF-beta1 in RA (P < 0.005), in OMF (P < 0.05) and in HZ (P < 0.05). Conclusion: These results support the concept that OET is beneficial in diseases characterized in part by TGF-beta1 overproduction.

3. Alpha 2-macroglobulin-mediated degradation of amyloid beta 1--42: a mechanism to enhance amyloid beta catabolism.

Lauer D, Reichenbach A, Birkenmeier G. Institute of Biochemistry, University of Leipzig, Liebigstrasse 16, 04103 Leipzig, Germany. Exp Neurol. 2001 Feb;167(2):385-92.

Peptides derived from proteolytic degradation of the amyloid precursor protein, e.g., amyloid beta (A beta), are considered to be central to the pathology of Alzheimer's disease (AD). Soluble A beta is present in measurable concentrations in cerebrospinal fluid and blood. There are indications that soluble A beta present in circulation can cross the blood-brain barrier via transcytosis mediated by brain capillary endothelial cells. It implies that A beta originating from circulation may contribute to vascular and parenchymal A beta deposition in AD. Enhancing of A beta catabolism mediated by proteolytic degradation or receptor-mediated endocytosis could be a key mechanism to maintain low concentrations of soluble A beta. To launch A beta clearance we have exploited the A beta-degrading activity of diverse alpha 2-macroglobulin (alpha 2-M)-proteinase complexes. Complexes with trypsin, alpha-chymotrypsin, and bromelain strongly degrade (125)I-A beta 1--42 whereas complexes with endogenous proteinases, e.g., plasmin and prostate-specific antigen, were not effective. A beta degradation by the complexes was not inhibited by alpha 1-antichymotrypsin and soybean trypsin inhibitor which normally would inactivate the free serine proteinases. A prerequisite for A beta degradation is its binding to specific binding sites in alpha 2-M that may direct A beta to the active site of the caged proteinase. Ex vivo, enhanced degradation of (125)I-A beta 1--42 in blood could be achieved upon oral administration of high doses of proteinases to volunteers. These results suggest that up-regulation of A beta catabolism could probably reduce the risk of developing AD by preventing A beta accumulation in brain and vasculature. Copyright 2001 Academic Press.

4. Intestinal absorption of undegraded proteins in men: presence of bromelain in plasma after oral intake.

Castell JV, Friedrich G, Kuhn CS, Poppe GE. Unidad de Hepatologia Experimental, Hospital Universitario La Fe, Valencia, Spain. Am J Physiol. 1997 Jul;273(1 Pt 1):G139-46. PMID: 9252520 [PubMed - indexed for MEDLINE]

The human adult intestinal epithelium has traditionally been described as nonpermeable to proteins. However, indirect evidence suggests that reduced absorption of undegraded proteins might take place under physiological conditions. Using bromelain (an enzyme obtained from pineapple stems) as a model protein, we studied the extent of this mucosal permeation in 19 healthy men. The protein was detected in plasma by immunoassay and by its proteolytic activity after oral administration. The estimated plasma half-life was 6-9 h. After oral multidosing (3 g/day), plasma concentration reached as much as 5,000 pg/ml by 48 h. From the plasma concentration curve, it could be estimated that an average of 10.8 micrograms of bromelain was present in plasma in the 3- to 51-h period. The presence of undegraded bromelain in plasma was shown unequivocally by immunoprecipitation of plasma samples with antibromelain antibodies, followed by gel electrophoresis and immunodetection. Moreover, the enzyme retained its biological activity, at least in part. Circulating bromelain was found associated with alpha 2-macroglobulin and alpha 1-antichymotrypain. The results of this work confirm the existence of a small but significant intestinal transport of undegraded proteins in healthy men.

Diverse role of LDL receptor-related protein in the clearance of proteases and in signaling.

Strickland DK, Ranganathan S. Department of Vascular Biology, Jerome H. Holland Laboratory for the Biomedical Sciences, American Red Cross, Rockville, MD, USA. J Thromb Haemost. 2003 Jul;1(7):1663-70. PMID: 12871303 [PubMed - indexed for MEDLINE]

The low density lipoprotein receptor-related protein (LRP) is a large endocytic receptor that participates in several biological pathways and plays prominent roles in lipoprotein metabolism and in the catabolism of proteinases involved in coagulation and fibrinolysis. LRP also mediates the cellular entry of certain viruses and toxins and facilitates the activation of various lysosomal enzymes. Deletion of the LRP gene in mice is lethal, confirming an important role for this receptor in development, although its exact function in development is still not known. In addition to its role in the endocytosis of numerous ligands, recent studies are emerging that describe a signaling role for this receptor as well.



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