Control of Interleukin-1β Secretion in Inflammation and Immune Response

Abstract

Intercellular communications are fundamental for a correct progression of immuno inflammatory responses. Major messengers in this network of information are cytokines, secretory proteins produced by immune and inflammatory cells. Blocking the function of pro-inflammatory cytokines has entered the clinical arena of treating autoimmune diseases. However, many cytokines including Interleukin (IL)-1, IL-18, HMGB1, belong to the family of "leaderless secretory proteins", that leave the cells through pathways independent from the classical Endoplasmic Reticulum (ER)-Golgi route. Thus, a successful outcome of an approach aimed at inhibiting cytokine activity requires a clear definition of the mechanisms controlling their release. In this article we will review current hypotheses on the mechanisms underlying non classical secretion and discuss their implications in the regulation of the inflammatory and immune response. In particular, we will dissect the sequence of events required for IL-1β secretion and describe some members of the molecular machinery involved, which could provide novel targets whereby control of IL-1β production may be achieved.

Active Caspase-1 Is a Regulator of Unconventional Protein Secretion

“…Unconventional secretion has been a mystery since its discovery but can be clearly distinguished from the classical secretion pathway. Nevertheless, a generally accepted mechanism of leaderless secretion is still missing, although several models exist (Andrei et al, 2004;Carta et al, 2006;MacKenzie et al, 2001;Nickel, 2005;Qu et al, 2007;Rubartelli, 2005). It seems to be a fast process, making it difficult to track proteins during their release.…”

“…We verified caspase-1-dependent secretion for uncleaved Bid, Aip-1/Wdr-1, annexin A2, and peroxiredoxin-1. Secretion of the leaderless protein thioredoxin-1 (Rubartelli, 2005) was also dependent on caspase-1, although its iTRAQ ratio suggested a caspase-1-independent secretion. In addition, caspase-1-independent release or secretion was verified for b-actin, gelsolin, and FGF-BP.…”

“…Interestingly, seven of them are known to be secreted via an ER/Golgi-independent pathway. They include annexin A2 (Danielsen et al, 2003), peroxiredoxin-1 (Chang et al, 2006), thymosin b-10 ( Huang et al, 2006a), cystatin-A (Heidtmann et al, 1997), HMGI-C/HMGA2 (Donaldson et al, 1998), as well as macrophage migration inhibitory factor (MIF) and galectin-3 (Rubartelli, 2005;Nickel, 2005). Eight other proteins harbor a signal peptide.…”

“…ProIL-1b, proIL-18, and -33 lack a signal peptide, and they are secreted by an unconventional, endoplasmic reticulum (ER)/ Golgi-independent pathway, which is poorly characterized (Qu et al, 2007;Ogura et al, 2006;Donaldson et al, 1998;Dinarello, 2002;Carta et al, 2006;Andrei et al, 2004). Several other leaderless but secreted proteins have been identified, which may leave the cell by a similar pathway as IL-1b (Cleves, 1997;Nickel, 2005;Rubartelli, 2005). Some of them, e.g., the proangiogenic growth factor FGF-2 (basic FGF), clearly fulfill an extracellular function, whereas such a function is less obvious for annexins 1 and 2, galectins, or EBBP/TRIM16 (Rubartelli, 2005;Nickel, 2005;Feldmeyer et al, 2007;Cleves, 1997).…”

“…Several other leaderless but secreted proteins have been identified, which may leave the cell by a similar pathway as IL-1b (Cleves, 1997;Nickel, 2005;Rubartelli, 2005). Some of them, e.g., the proangiogenic growth factor FGF-2 (basic FGF), clearly fulfill an extracellular function, whereas such a function is less obvious for annexins 1 and 2, galectins, or EBBP/TRIM16 (Rubartelli, 2005;Nickel, 2005;Feldmeyer et al, 2007;Cleves, 1997). Interestingly, caspase-1 and other inflammasome proteins are also released from activated macrophages or UV-irradiated keratinocytes, although all these proteins lack a signal peptide (Martinon et al, 2002;Martinon and Tschopp, 2004;Mariathasan et al, 2004;Feldmeyer et al, 2007).…”