Asthma is a major public health problem. T cell-mediated airway inflammation plays a major role in chronic asthma. Although much is known about the mechanism of initiation of inflammation, less is known about the mechanism of its persistence. Acute inflammation usually resolves due to negative homeostatic regulation. In preliminary studies we observed increased T cell proliferation in asthma. This proliferation is refractory to anergy induction and to the action of the negative regulators-TGF-beta and IL-10. In exploring the mechanism of this refractoriness we observed that T cells from asthmatic patients express increased levels of the signaling kinase MEK1, which stimulates IL-2 production. Interestingly, IL-2 directly induces MEK1. Our hypothesis is that the IL-2 driven MEK1 expression establishes a positive feedback mechanism that drives heightened T cell proliferation and overrides the negative regulation in asthma. We also hypothesize that MEK1, in addition to activating ERK1/2 in the cytosol, inhibits the gene repressor SMRT in the nucleus, which primes inflammatory gene transcription in T cells. We propose 3 specific aims.
Under specific aim 1 we will study the mechanism of increased MEK1 expression in T cells from asthma. We will examine the contribution of various cytokines and co-stimulatory molecules. We will also examine the signaling processes that lead to MEK1 expression. We will perform studies with human blood T cells as well as normal and genetically modified mouse T cells.
Under specific aim 2 we will study the role of nuclear MEK1 in T cell function, examine its inhibitory effect on the gene repressor SMRT, dissect the independent role of nuclear MEK1 and ERK1/2 in regulating SMRT and Ets transcription factors at the c-Fos gene promoter, and finally, investigate the role of SMRT in T cell function from asthmatic patients. These studies will involve gene manipulations, chromatin immunoprecipitation, and T cell functional studies.
Under specific aim 3 we will examine the contribution of MEK1 and IL-2 to the persistence of airway inflammation in a mouse model of asthma. We have specifically developed a mouse model of chronic asthma, which mimics human asthma in many respects. We will examine genetically modified mouse strains and/or T cells, and an anti-IL2 receptor (anti-CD25) antibody for their effect on airway hyperreactivity, inflammation, mucus production and airway remodeling in this chronic asthma model. The proposal is important because it addresses the mechanism of persistence of airway inflammation in asthma. The results of this study will lead to the development of novel therapeutic modalities for asthma.
Asthma is a major public health problem. One of the important features of asthma is chronic inflammation. This research proposal will examine the mechanism of persistence of this inflammation in asthma. An understanding of chronic inflammation may help develop novel therapeutic modalities for asthma.
|Alam, Rafeul; Good, James; Rollins, Donald et al. (2017) Airway and serum biochemical correlates of refractory neutrophilic asthma. J Allergy Clin Immunol 140:1004-1014.e13|
|Liu, Weimin; Liu, Sucai; Verma, Mukesh et al. (2017) Mechanism of TH2/TH17-predominant and neutrophilic TH2/TH17-low subtypes of asthma. J Allergy Clin Immunol 139:1548-1558.e4|
|Christianson, Christina A; Goplen, Nicholas P; Zafar, Iram et al. (2015) Persistence of asthma requires multiple feedback circuits involving type 2 innate lymphoid cells and IL-33. J Allergy Clin Immunol 136:59-68.e14|
|Alam, Rafeul (2015) Reply: To PMID 25042748. J Allergy Clin Immunol 135:291|
|Germinaro, Matthew; Reynolds, Paul; Knight, Vijaya et al. (2015) Association of B-cell activating factor receptor deficiency with the P21R polymorphism and common variable immunodeficiency. Ann Allergy Asthma Immunol 115:82-3|
|Alam, Rafeul (2014) Obesity and asthma--is there a causal association? Immunol Allergy Clin North Am 34:xi-xii|
|Manners, Sarah; Alam, Rafeul; Schwartz, David A et al. (2014) A mouse model links asthma susceptibility to prenatal exposure to diesel exhaust. J Allergy Clin Immunol 134:63-72|
|Czaja, Christopher A; Merkel, Patricia A; Chan, Edward D et al. (2014) Rituximab as successful adjunct treatment in a patient with disseminated nontuberculous mycobacterial infection due to acquired anti-interferon-? autoantibody. Clin Infect Dis 58:e115-8|
|Schulten, Véronique; Tripple, Victoria; Sidney, John et al. (2014) Association between specific timothy grass antigens and changes in TH1- and TH2-cell responses following specific immunotherapy. J Allergy Clin Immunol 134:1076-83|
|Alam, Rafeul (2014) Urticaria: an evolving story. Immunol Allergy Clin North Am 34:xiii-xiv|
Showing the most recent 10 out of 32 publications