Synergistic and feedback signaling mechanisms in the regulation of inflammation in respiratory infections.
Pneumonia, the most typical and frequent lower respiratory tract infection (LRTI), is a leading cause of health problems in the United States. Bacteria represent the most prevailing cause of pneumonia in both children and adults. Although pneumonia with a single bacterial infection is common, a significant portion of patients with pneumonia is polymicrobial. This infection is often complexed with other physiological factors such as cytokines and growth factors. Nontypeable Haemophilus influenzae (NTHi) is the most frequently recovered Gram-negative bacterial pathogen in the respiratory system and induces strong inflammatory responses. NTHi also synergizes with other respiratory pathogens, such as Streptococcus pneumoniae and respiratory viruses and pro-inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-α). It is noteworthy that NTHi not only synergizes with growth factors such as transforming growth factor-beta (TGF-β), but also utilizes growth factor receptors such as TGF-β receptor and epidermal growth factor receptor (EGFR), to enhance inflammatory responses. Although appropriate inflammation is a protective response against invading pathogens, an uncontrolled inflammatory response is often detrimental to the host. Thus, inflammation must be tightly regulated. The human immune system has evolved strategies for controlling overactive inflammatory response. One such important mechanism is via regulation of negative feedback regulators for inflammation. CYLD, a multifunctional deubiquitinase, was originally reported as a tumor suppressor, but was recently identified as a negative regulator for nuclear factor-kappa B (NF-κB) signaling. It is induced by NTHi and TNF-α via a NF-κB-dependent mechanism, thereby serving as an inducible negative feedback regulator for tightly controlling inflammation in NTHi infection.
Center for Inflammation, Immunity and Infection, and Department of Biology, Georgia State University, Atlanta, GA 30302, USA.
Wenzhuo Y
WY
Wang
Jae Hyang
JH
Lim
Jian-Dong
JD
Li
D000818:Animals; D000074749:Deubiquitinating Enzyme CYLD; D066246:ErbB Receptors / Q000378:metabolism; D025461:Feedback, Physiological; D006192:Haemophilus Infections / Q000150:complications / Q000276:immunology*; D006193:Haemophilus influenzae / Q000276:immunology* / Q000472:pathogenicity; D006801:Humans; D016328:NF-kappa B / Q000378:metabolism; D011008:Pneumococcal Infections / Q000150:complications / Q000276:immunology*; D018410:Pneumonia, Bacterial / Q000276:immunology* / Q000382:microbiology*; D012137:Respiratory System / Q000276:immunology / Q000382:microbiology; D015398:Signal Transduction / Q000276:immunology; D013296:Streptococcus pneumoniae / Q000276:immunology* / Q000472:pathogenicity; D016212:Transforming Growth Factor beta / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000276:immunology*; D044767:Ubiquitin-Protein Ligases / Q000276:immunology
D016328:NF-kappa B; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; D025521:Tumor Suppressor Proteins; D044767:Ubiquitin-Protein Ligases; D066246:ErbB Receptors; C409984:CYLD protein, human; D000074749:Deubiquitinating Enzyme CYLD