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5 Functions as a Regulator of Inflammatory Immune Responses via TNF-mediated Signaling1
,
* Divisions of Pulmonary and Critical Care Medicine and
Renal Division, Department of Medicine, and Departments of
Pathology and Immunology and
Cell Biology and Physiology, Washington University School of Medicine and Barnes-Jewish Hospital, St. Louis, MO 63110
Tissue injury triggers inflammatory responses that may result in release of degradation products or exposure of cryptic domains of extracellular matrix components. Previously, we have shown that a cryptic peptide (AQARSAASKVKVSMKF) in the 
-chain of laminin-10 (5
1
1), a prominent basement membrane component, is chemotactic for both neutrophils (PMNs) and macrophages (M
s) and induces matrix metalloproteinase-9 (MMP-9) production. To determine whether AQARSAASKVKVSMKF has additional effects on inflammatory cells, we performed microarray analysis of RNA from RAW264.7 Ms stimulated with AQARSAASKVKVSMKF. Several cytokines and cytokine receptors were increased >3-fold in response to the laminin 5 peptide. Among these were TNF- and one of its receptors, the p75 TNFR (TNFR-II), increasing 3.5- and 5.7-fold, respectively. However, the peptide had no effect on p55 TNFR (TNFR-I) expression. Corroborating the microarray data, the protein levels of TNF- and TNFR-II were increased following stimulation of RAW264.7 cells with AQARSAASKVKVSMKF. In addition, we determined that the production of TNF- and TNFR-II in response to AQARSAASKVKVSMKF preceded the production of MMP-9. Furthermore, using primary Ms from mice deficient in TNFR-I, TNFR-II, or both TNF- receptors (TNFRs), we determined that AQARSAASKVKVSMKF induces MMP-9 expression by Ms through a pathway triggered by TNFR-II. However, TNF- signaling is not required for AQARSAASKVKVSMKF-induced PMN release of MMP-9 or PMN emigration. These data suggest that interactions of inflammatory cells with basement membrane components may orchestrate immune responses by inducing expression of cytokines, recruitment of inflammatory cells, and release of proteinases.
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