| First Author | Saxena A | Year | 2013 |
| Journal | J Immunol | Volume | 191 |
| Issue | 9 | Pages | 4838-48 |
| PubMed ID | 24078695 | Mgi Jnum | J:206237 |
| Mgi Id | MGI:5548252 | Doi | 10.4049/jimmunol.1300725 |
| Citation | Saxena A, et al. (2013) IL-1 induces proinflammatory leukocyte infiltration and regulates fibroblast phenotype in the infarcted myocardium. J Immunol 191(9):4838-48 |
| abstractText | In the infarcted myocardium, activation of the inflammatory cascade clears the wound from dead cells, whereas stimulating matrix degradation and chamber dilation, thus contributing to the development of heart failure. IL-1 is critically involved in the postinfarction inflammatory reaction and mediates adverse dilative remodeling. We hypothesized that IL-1 may regulate postinfarction repair and remodeling through cell-specific actions on leukocytes and fibroblasts. Flow cytometry demonstrated that in mouse infarcts, early recruitment of proinflammatory Ly6C(hi) cells expressing IL-1R1, the signaling receptor for IL-1, was followed by infiltration with cells expressing the decoy receptor, IL-1R2. Increased expression of IL-1R2 may serve to terminate IL-1-driven inflammation after infarction. Loss of IL-1 signaling in IL-1R1 null mice globally attenuated leukocyte recruitment, reducing the number of infiltrating Ly6C(hi) and Ly6C(lo) cells. Nonmyeloid CD11b(-) cells harvested during the inflammatory phase of cardiac repair exhibited marked upregulation of chemokines and cytokines; their inflammatory activation was IL-1R1 dependent. Moreover, IL-1beta attenuated TGF-beta-induced contractile activity of fibroblasts populating collagen pads, attenuated alpha-smooth muscle actin expression, and stimulated matrix metalloproteinase synthesis in an IL-1R1-dependent manner. The effects of IL-1 on TGF-beta responses in cardiac fibroblasts were not due to direct effects on Smad activation, but were associated with endoglin suppression and accentuated expression of bone morphogenetic protein and activin membrane-bound inhibitor, a negative regulator of TGF-beta signaling. IL-1 may orchestrate fibroblast responses in the infarct; early stimulation of fibroblast IL-1R1 signaling during the inflammatory phase may prevent premature activation of a matrix-synthetic contractile phenotype until the wound is cleared, and the infarct microenvironment can support mesenchymal cell growth. |
