AbstractPurpose Overnight eye closure results in a near cessation in tear turnover and the induction of a sub‐clinical inflammation as evidenced by PMN cell recruitment and degranulation and the accumulation of pro‐inflammatory cytokines and chemokines. What prevents cytokine induced damage to the cornea was investigated.Methods Methods: Open (O) and Closed (C) tears from Ns were subjected to multiple micro well array assays to obtain quantitative data on the distribution of >80 low abundance proteins. Samples were also separated by molecular sieve HPLC and the eluent profiled for the presences of chemokines, cytokines and interactive proteins. Cytokine‐protein complexes were identified using a laboratory‐developed multiplex assays.Results Micro‐well array assay reveal a marked increase in the concentrations of a wide range of inflammatory and immune modulating cytokines as well as chemokines in the closed eye tears. This was accompanied by increased levels of s‐receptors at concentrations greatly exceeding that of the targeted proteins along with the accumulation of α2‐M. Protein‐protein binding studies and analysis of the HPLC eluent reveals that most inflammatory, angiogenic and immune cytokines eluent in the form of macromolecular complexes bound to s‐receptor and α2‐M. This serves to inactivate these entities and tags them for up take by macrophages and other cells that express the α2‐M receptor. In contrast chemokines which lack s‐receptors remain free and bioactive.Conclusion s‐receptors and α2‐M co‐operatively function in the down–regulation of cytokine and growth factor induced inflammation. Data will also be presented showing its functional role in the control of inflammation elsewhere.