Objective: The purpose of these studies is to investigate the role of integrin binding on the regulation of polymorphonuclear leukocyte (PMN) cytokine receptor expression. Summary Background Data: Current knowledge in this area revolves around the ability of β2 integrins to mediate PMN adherence and chemotaxis. The role of α1-6/β1 integrins in regulating cytokine receptor expression has not been probed. Methods: Purified human PMN were adhered on plastic, fibronectin, or laminin-coated surfaces followed by the addition of iodine f 25 (125I) monoclonal antibodies (mAbs) directed against tumor necrosis factor-αR (TNF-αR) p60, p80, or interleukin-1βR (IL-1βR) types I, II. Receptor expression was calculated based on the counts per minute (cpm) bound. The role of individual β1 integrins was assessed using mAbs directed against the α1-6 subunit of the β1 complex, and integrin cross-linkage was achieved using secondary goat antimouse F(ab')2 antibodies. Polymorphonuclear leukocytes were pretreated with herbimycin A to determine the role of protein tyrosine kinase in mediating the effect of the β1 integrins. Results: Adherence of PMN to Ln decreased IL-1β types I, II receptor expression, whereas adherence to Fn increased TNF-αR p60 and p80 expression. Anti-VLA-5 (CD49e) but not anti-VLA-1 through VLA-4 and VIA-6, blocked the effect of Fn on TNF-α receptors, whereas anti-VLA-6 but not anti-VLA-1 through VLA-5 blocked the effect of Ln on IL-1β receptors. Modulation of IL-1β and TNF-α receptors by VLA-5 and VLA-6 required protein tyrosine kinase activation as herbimycin A (10 μg/mL) blocked the affect of Fn and Ln. Changes in PMN cytokine receptor expression led to parallel changes in functional activity as assessed by the binding of 125I IL-1β and TNF-α. Conclusions: Integrin stimulation regulates the cell surface expression of PMN cytokine receptors. Ligation of CD49e upregulates TNF-α receptor expression, whereas binding of CO49f downregulates IL-1β receptor expression. Both processes are protein tyrosine kinase dependent. Changes in PMN cytokine receptor expression led to corresponding changes in functional activity. These results provide the first demonstration that chemotaxis of PMN into the interstitium provides a mechanism for ongoing participation in the local inflammatory response and is regulated by matrix protein integrin receptors.