Steven Kunkel, Ph.D.
Senior Associate Dean of Research
Endowed Professor, Department of Pathology
Co-Director, Division of Sponsored Programs

slkunkel@umich.edu

Experimental research activities directed at understanding cytokine networks that are operative in a variety of inflammatory reactions and host defenses represent the major investigative directions of my laboratory. Specific studies are designed to assess the expression and regulation of both proximal mediator, such as Interleukin-1 (IL-1) and Tumor Necrosis Factor-alpha (TNF) and more distal mediators, such as Interleukin-8 (IL-8) and monocyte chemoattractant protein-1 (MCP). Investigations have identified that macrophage-derived IL-1 and TNF can serve as early inflammatory gene products which set in motion a cascade of events resulting in the expression of chemokines from a variety of non-immune cells. Fibroblasts, epithelial cells, hepatocytes, and endothelial cells can all express chemokines when stimulated with either macrophage condition media, IL-1, or TNF. The ability of non-immune structural cells to express chemotactic cytokines is likely to play a fundamental role in host defense and provide a mechanism for the localization of many acute and chronic inflammatory responses. While IL-1 and TNF appear to cause a pro-inflammatory response by initiating cytokine cascades, other cytokines may result in negative effects resulting in the down-regulation of cytokines and their cascades. These latter regulatory polypeptide mediators include interleukin-1 receptor antagonist, IL-4, IL-10, IL-13, and soluble cytokine receptors. During the evolution of chronic inflammation these signals are likely to mediate the switch between maintenance of the response and progression to fibrosis to resolution of the inflammatory reaction.

Representative Publications:

Ishii M, Wen H, Corsa CA, Liu T, Coelho AL, Allen RM, Carson WF 4th, Cavassani KA, Li X, Lukacs NW, Hogaboam CM, Dou Y, Kunkel SL. Epigenetic regulation of the alternatively activated macrophage phenotype. Blood. 2009 Jun 30. [Epub ahead of print] PMID: 19567879.

Ito T, Schaller M, Hogaboam CM, Standiford TJ, Sandor M, Lukacs NW, Chensue SW, Kunkel SL. TLR9 regulates the mycobacteria-elicited pulmonary granulomatous immune response in mice through DC-derived Notch ligand delta-like 4. J Clin Invest. 2009 Jan;119(1):33-46. Epub 2008 Dec 15. PMID: 19075396; PMCID: PMC2613456.

Cavassani KA, Ishii M, Wen H, Schaller MA, Lincoln PM, Lukacs NW, Hogaboam CM, Kunkel SL. TLR3 is an endogenous sensor of tissue necrosis during acute inflammatory events. J Exp Med. 2008 Oct 27;205(11):2609-21. Epub 2008 Oct 6. PMID: 18838547; PMCID: PMC2571935.

Ishii M, Hogaboam CM, Joshi A, Ito T, Fong DJ, Kunkel SL. CC Chemokine receptor 4 modulates Toll-like receptor 9-mediated innate immunity and signaling. Eur J Immunol. 2008. Aug;38(8):2290-302.

Wen H, Dou Y, Hogaboam CM, Kunkel SL. Epigenetic regulation of dendritic cell-derived interleukin-12 facilitates immunosuppression after a severe innate immune response. Blood. 2008 Feb 15;111(4):1797-804.

Wen H, Schaller MA, Dou Y, Hogaboam CM, Kunkel SL. Dendritic cells at the interface of innate and acquired immunity: the role for epigenetic changes. J Leukoc Biol. 2008 Mar;83(3):439-46.

Raymond T, Schaller M, Hogaboam CM, Lukacs NW, Rochford R, Kunkel SL. Toll-like receptors, Notch ligands, and cytokines drive the chronicity of lung inflammation. Proc Am Thorac Soc. 2007 Dec;4(8):635-41.

Coelho AL, Schaller MA, Benjamim CF, Orlofsky AZ, Hogaboam CM, Kunkel SL. The chemokine CCL 6 promotes innate immunity via immune cell activation and recruitment. J Immunol. 2007 Oct 15;179(8):5475-82.

Ito T, Schaller M, Hogaboam CM, Standiford TJ, Chensu SW, Kunkel SL. TLR9 activation is a key event for the maintenance of a mycobacterial antigen-elicited pulmonary granulomatous response. Eur J Immunol. 2007 Oct;37(10):2847-55.

Wen H, Hogaboam CM, Lukacs NW, Cook DN, Lira SA, Kunkel SL. The chemokine receptor CCR 6 is an important component of the innate immune response. Eur J Immunol. 2007 Sep;37(9):2487-98.

Rudd BD, Schaller MA, Smit JJ, Kunkel Sl, Neupane R, Kelley L, Berline AA, Lukacs NW. MyD88-mediated instructive signals in dendritic cells regulate pulmonary immune responses during respiratory virus infection. J Imminol 2007; 178:5820-5827.

Hochreiter R, Ptaschinski C, Kunkel SL , Rochford R. Murine gammaherpesvirus-68 productively infects immature dendritic cells and blocks maturation. J Gen Virol 2007; 88:1896-1905.