Cystatin protease inhibitors and immune functions

Abstract

Cystatins are natural tight-binding reversible inhibitors of cysteine proteases. They are wide spread in all living organisms (mammals, nematodes, arthropods etc.) and are involved in various biological processes where they regulate normal proteolysis and also take part in disease pathology. Many cystatins show changes in expression and/or localization, as well as changes in secretion, following certain stimuli acting on immune cells. In immune cells, cystatins interfere with antigen processing and presentation, phagocytosis, expression of cytokines and nitric oxide and these ways modify the immune response. Further, it has been suggested that cystatin-type molecules secreted from parasites down-modulate the host immune response. Precise understanding of the regulatory roles on proteolytic enzymes of endogenous and exogenous cystatins, such as those from parasites, will provide us with valuable insight into how immune response could be modulated to treat a specific disease. This review covers some specific functions of individual cystatins, with a particular focus on the relevance of cystatins to the immune response.

Cystatins, cysteine peptidase inhibitors, as regulators of immune cell cytotoxicity

“…They contain approximately 350 amino acid residues, have eight disulphide bonds and are glycosylated. They are secreted extracellularly and found intravascularly, where they provide systemic protection against leaking endolysosomal cysteine peptidases (43,44).…”

“…In addition to inhibiting endogenous cysteine peptidases, they can also inhibit cysteine peptidases from microorganisms and parasites, helping in defence against microbial infections (44). Furthermore, cystatins can also act independently from their inhibitory function; for example cystatin C was shown to interact with transforming growth factor b (TGF-b) type II receptor, thus interfering with TGF-b binding (45).…”

“…Like most type II cystatins it is secreted and found at high levels in body fluids, where it most probably acts as an emergency inhibitor, neutralizing redundant proteolytic activity outside cells (44,51). It has diagnostic and prognostic value in several diseases; for example it is a marker of glomerular filtration rate and thus of kidney function (51).…”

Immunomodulatory and Antibacterial Effects of Cystatin 9 against Francisella tularensis

“…Cystatins are structurally conserved, low molecular weight endogenous cysteine protease inhibitors found in most body compartments and fluids. Characteristically, they are described to function intra-and/or extracellularly to inhibit their target cysteine enzymes (for example, cathepsins) to maintain a crucial protease-inhibitor balance, thus regulating damaging proteolytic activities (2,3). Distinct cystatins regulate specific cysteine proteases.…”

“…Under pathophysiological conditions, dysregulated inflammatory responses can cause decreased levels of cystatins that are insufficient to regulate proteases (1,(7)(8)(9). This, in turn, results in excessive cytokine production, unrestrained tissue breakdown (for example, degradation of the extracellular matrix [ECM]) and promotes excessive immune cell extravasation to inflammation sites exacerbating organ damage (1,3,(7)(8)(9).…”