G lutamine and Heat Shock Proteins in Immunity and Inflammation
Heat Shock Proteins
Heat shock proteins (HSPs) are highly conserved proteins functioning in the unstressed state as intracellular molecular chaperones, maintaining homeostatic function, including protein refolding, movement of proteins across membranes, and gene regulation (Leppa and Sistonen, 1997). Cellular stress affects protein homeostasis resulting in misfolding and clumping of proteins (both self and nonself). The HSP response has evolved with the principal task of restoring protein homeostasis: repairing damage to proteins and re-establishing normal growth conditions (Wu, 1995; Leppa and Sistonen, 1997; Morimoto and Santoro, 1998; Laramie et al., 2008). HSPs are involved in numerous biological processes including the cell cycle, cell proliferation, differentiation, and apoptosis (Milarski and Morimoto, 1986; Hang et al., 1995). Numerous HSPs have been described and subsequently have been classified into six main families: HSP27, HSP40, HSP60, HSP70, HSP90, and HSP110. Of these, the HSP70 family is one of the most well studied and understood (Milarski and Morimoto, 1986; Jerome et al., 1993; Hang et al., 1995; Jaattela, 1999).
HSP70 is constitutively expressed and required at all times for cells to function normally. It is present in various cells including embryo cells, glial cells, dendritic cells (DCs), endothelial cells, monocytes, granulocytes, macrophages, B and T lymphocytes, and vascular smooth muscle cells (Hunter-Lavin et al., 2004). HSP70 comprises 1%-5% of cellular protein and is found in the cytoplasm, nucleus, mitochondria, and endoplasmic reticulum (Morimoto and Santoro, 1998).
HSP70 also occurs in an inducible form (Nam et al., 2007). The heat shock response is rapid, occurring within minutes of stress recognition (Morimoto and Santoro, 1998), resulting in the ubiquitous release of HSP70 (Maugeri et al., 2010). HSP70 is released in response to environmental stress (e.g., heat shock, heavy metals, oxidative stress) and pathological stress (e.g., ischemic and reperfusion injury and inflammatory response) (Laramie et al., 2008). Cytoplasmic HSP70 accumulation is relative to the degree of cellular stress (Morimoto and Santoro, 1998), conferring cyto- protection, in addition to acting as an extracellular chemokine to neighboring cells. Under these circumstances inducible HSP70 can comprise up to 20% of cell protein content (Pockley et al., 2008). HSP70 also acts to increase phagocytosis and uptake of foreign antigens and upregulates costimulatory molecules (de Jong et al., 2009).
Elevated levels of HSP70 remain within the cell for several hours conferring protection from subsequent insults (Balakrishnan and De Maio, 2006). However, ongoing HSP70 expression in an unstressed state has been found to be detrimental to cells and as a result mechanisms have evolved to ensure the timely resolution of the heat shock response (Li et al., 1991; Arispe et al., 2004).