IL-4 and IFN-γ Up-Regulate Substance P Receptor Expression in Murine Peritoneal Macrophages

Abstract

While the ability of macrophages to express authentic substance P receptors (i.e., NK-1 receptors) has been inferred from radioreceptor binding assays and functional assays and, most recently, by identification of NK-1 receptor mRNA expression, we know little about NK-1 expression at the protein level or what host factors might up-regulate expression of this receptor. In the present study we demonstrate that the cytokines IL-4 and IFN-γ can increase the expression of NK-1 receptors on murine peritoneal macrophages. Specifically, we show that IL-4 and IFN-γ can elicit increases in the level of mRNA encoding the NK-1 receptor by up to 12- and 13-fold, respectively. Furthermore, these cytokines can significantly increase the expression of the NK-1 receptor protein as measured by Western blot and FACS analysis using specific Abs developed in our laboratory. In addition, we have demonstrated the ability of both IL-4 and IFN-γ to enhance the ability of macrophages to bind substance P as measured by radiolabeled binding assay. The observation that the level of expression of this receptor protein can be enhanced by cytokines that promote either cell-mediated (Th1) or humoral (Th2) immune responses supports the idea that this receptor can be induced during either type of immune response. As such, these results may point to a more ubiquitous role for substance P in the generation of optimal immune responses than previously appreciated.

Substance P Regulates Th1-Type Colitis in IL-10 Knockout Mice

“…As shown in this report, one point of control is through transcriptional regulation of the biosynthesis of its natural ligand NK-1R (12,26). Also, engagement of SP with its receptor at the cell surface results in temporary receptor desensitization and loss of bioavailability.…”

Full-length and truncated neurokinin-1 receptor expression and function during monocyte/macrophage differentiation

“…SP increases the functional phagocytic response in macrophages and other phagocytes (4). SP specifically activates NF-B, a key transcriptional factor involved in the control of cytokine expression (5,6). SP stimulates immune cells to produce inflammatory cytokines, including IL-1, IL-6, TNF-␣ (1), IFN-␥ (7), and macrophage inflammatory protein 1␤ (8), which are important constituents of immune cell activation and act as physiological induction signals in the regulation of immune responses.…”

Chemical sympathectomy increases susceptibility to ocular herpes simplex virus type 1 infection

“…For example, substance P elicits the production of cytokines including TNF-α (Lotz et al, 1988), and IFN-γ (Lighvani et al, 2005) which are linked to the control of HSV-1 infection. As T and B lymphocytes and monocyte/macrophages express the NK1R (Stanisz et al, 1987;Pascual et al, 1992;Marriott and Bost, 2000), it has been suggested substance P may serve to optimize the local inflammatory response (Marriott and Bost, 2000) which may facilitate the clearance of pathogens (Brogden et al, 2005;Svensson et al, 2005) but have detrimental consequences relative to sites sensitive to inflammation as is the case of rheumatoid arthritis (Miller et al, 2000) and most likely, the CNS. In contrast to what has been reported, we found an elevation in substance P was associated with a reduction of IFN-γ in the TG but not BS of HSV-1-infected, sympathectomized mice.…”