Roles of caspase 1 and extracellular signal-regulated kinase in inflammation-induced inhibition of lacrimal gland protein secretion.

Sjogren syndrome, a systemic inflammatory autoimmune disease, is the leading cause of the aqueous tear- deficient type of dry eye.1,2 Sjogren syndrome may be a primary disorder (primary Sjogren syndrome), or it may be associated with other autoimmune diseases (secondary Sjogren syndrome) such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and systemic sclerosis. Lacrimal gland inflammation is also common in other autoimmune diseases such as diabetes, thyroid disease, and sarcoidosis.3 Other examples of pathologic conditions resulting in lacrimal gland inflammation (for a review, see Zoukhri3) include chronic graft-versus-host disease (cGVHD), acquired immunodeficiency syndrome, hepatitis C, and aging. Increased production of autoantibodies and proinflammatory cytokines, both of which are believed to interfere with tear production, are common in inflammatory disease of the lacrimal gland. Our previous research showed that IL-1 plays a major role in impairing lacrimal gland secretion.4 IL-1 is a potent proinflammatory cytokine and consists of two isoforms, α and β, and a specific receptor antagonist, IL-1ra.5,6 Both IL-1α and IL-1β are synthesized as 31-kDa precursors without leader sequence.5,6 In contrast to IL-1α, IL-1β is only active in its secreted mature form (17.5 kDa). The IL-1β– converting enzyme (ICE), better known as caspase 1, cleaves the precursor protein at Asp116 to generate the mature active form of IL-1β.5,6 Caspase 1 is also synthesized as an inactive 45-kDa precursor, consisting of p20 and p10 subunits, and is proteolytically cleaved to generate an active enzyme comprising the p20 and p10 polypeptides.5,6 Various microbial agents such as lipopolysaccharide (LPS) are known to induce the activation of caspase 1.7–9 A study by Hirai et al.10 showed that injection of LPS into the lacrimal gland induced an inflammatory response that started 9 hours after injection and became severe at 24 hours. Because LPS is known to activate caspase 1,7–9 we hypothesized that LPS injection will inhibit lacrimal gland secretion by inducing the production of IL-1β through the activation of caspase 1. To test this hypothesis, the effect of LPS on lacrimal gland secretion and caspase 1 activity was investigated, as was the effect of a caspase 1 inhibitor. IL-1 has two receptors, a signaling receptor named IL-1RI and a decoy receptor named IL-1 RII that does not signal.5 Activation of the IL-1RI triggers a signaling cascade leading to the transcription of several genes involved in acute and chronic inflammation and connective tissue diseases.6 The effect of IL-1 on gene transcription can be mediated by the activation of one or more members of the mitogen-activated protein kinases (MAPK) family.11–13 In mammalian systems, at least six independent MAPK signaling units appear to function.14,15 Among them, the biochemical properties of three MAPKs, the extracellular signal-regulated kinases (ERK1/2), the c-Jun NH2-terminal kinases (JNK1/2), and the p38 MAPKs, have been characterized in some detail.14,15 Once ERK, JNK, and p38 MAPK are activated, they lead to the activation of two major transcription factors, activator protein 1 (AP-1) and nuclear factor-κB (NF-κB).14,15 In a recent study, we showed that JNK inhibition activated by exogenous addition of IL-1β alleviated the inhibitory effect exerted by this cytokine on lacrimal gland secretion and restored tear production in a murine model of aqueous tear- deficient dry eye.16 Hence, a second purpose of the present study was to investigate whether ERK signaling is involved in IL-1β–induced inhibition of lacrimal gland secretion.